Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
SB320/C
2078~0~
BENZ~NILIDE DERIVATIVES
This invention relates to novel benzanilide derivatives, to
processes for their preparation, and to pharmaceutical compositions
containing them
According to the invention we provide compounds of the general
formula (I) -
Rl R3
10 ` ,~CONH~
2 ~ R~ ~3
or a physiologically acceptable salt or solvate (eg hydrate)~thereof, in which
Rl represents a hydrogen atom or a halogen ato~ or a group selected
fro~ Cl_6alkyl and C1_6alkoxy;
R2 represents a phenyl group substituted by a group-sel ted from
R~ , ~ ~ ~ ~ aod
R
~: :
and-optionally further substituted by one or two substituents
selected from halogen atoms, Cl_6alkoxy, hydroxy, and C1_6alkyl;
R represents the group
- ~ - R7
R4 and R5, which may bo tho sa~o or difforent, each indopendently
30 represent a hydrog-n atom or a halogen atom or a group selected from
hydroxy, Cl_6alkoxy and Cl!_6alkyl;
R6 represents a hydrogen atom or a group selected from -NR9R10 and a
Cl_6alkyl group optionally substituted by one or two substituents
selected from Cl_6alkoxy, hydroxy, Cl_6acyloxy and -802Rll;
R7, R8 and R9, which may be the same or different, each
independently represent a hydrogen atom or a Cl_6alkyl group;
..
"' "~
: . :
- 5~320/c 2078~0~
~ 2 -
R10 represents a hydrogen atom or a group selected from C1_6alkyl,
Cl_6acyl, benzoyl and -So2Rll;
Rll represents a Cl_6alkyl group or a phenyl group;
z represents an oxygen atom or a group selected from NR8 and s(o)k;
and
k represents zero, 1 or 2.
It is to be understood that the present invention encompasses
all geo~etric and optical isomers of the compounds of gen-ral
for~ula (I) and their mixturcs including tbe racemic ~ixtures
thereof. ~
Physiologically acceptable salts of the compounds of general
formula (I) include acid addition salts for~ed with inorganic or
organic acids Ifor exa~ple hydrochlorides, hydrobro~ides, sulphates,
phosphates, benzoates, naphthoates, hydroxynaphthoates, ~-
toluenesulphonates, _ thanesulphonates, sulpha~ates, ascorbates,
tartrates, citrates, oxalates, maleatcs, salicylates, fu~Arates,
succinates, lactates, glutarates, g}utaconates, acetates or
tricarballylates).
In the compounds of geDeral for~ula (I), the ter~ 'Cl_6alkyl'
or 'Cl_6alkoxy' as a group or part of a group ~eans that the group
is straight or branched and consists of 1 to 6 carbon atoms.
Exa~ples of suitab}e alkyl groups include methyl, ethyl,;n-propyl,
i-propyl, n-butyl, s-butyl and t-butyl. ~xampIes of suitable alkoxy
group- include ~etXoxy, ethoxy, n-propoxy, i-propoxy, n:butoxy, s-
butoxy and t-butoxy. Th term 'halogen' within the definition of R2
means fluorine, chlorine, bromine or iodine.
In the compounds of general formula (I), the term 'acyl' as a
group or part of~a group ~eans an alkanoyl group such as acetyl or
pivaloyl. ~ ;
A proferrod group of co~pound- of gonoral for~ula (I) i- that
30 wherein the sub-tituent of for~ula
R6 ~ R6l R6J--~ Z ~
R
.
.
. . - . .
.
- `., ~ ~.
S~320/C ~078~0~
as defined above, on the phenyl group of R2 is attached at a
position meta or para to the bond to the phenyl ring A in general
formula (I~
A further preferred group of compound~ of general formula ~I)
is that wherein the substituent of formula
~ ~ N ~ ~ ~ ~ N ~ d
R8
on the phenyl group of R2 is attach-d at the position para to the
bond to the phenyl rinq A in general formula~(I)
Another preferred group of compounds of general formula (I) is
that wherein R~ is additionally substituted by one or two
substituents selected from halogen atom~, Cl-6alkoxy~ hydroxy and
Cl_6alkyl, which i8 ~are) attaohed at a position ortho to the bond
to the phenyl ring A in genal formula (I~
A further preferred group of compounds of general formula (I)
is that wherein R2 repre3ents a phenyl group ~ubstituted by the
20 substituent
R~
25 and optionally further sub~t~tuted by one or two substituents
selected fro~ halogen atoms, Cl_6alkoxy, hydroxy and Cl_6alkyl
`~Also preferred are those compounds of general formula (I)
;wherein R1 represents a hydrogen atom or a C1_6alkyl, e~pecially
methyl, group
Another preferret group of co~pounds of goneral formula (I) i~
30 that whorein Z ~epro-onts an oxygen atom
-A further preferred group of compounds of gene~al formula (I)~
is that wherein R6 represents a C1_6alkyl, especially methyl, group
optionally substituted by a Cl_6alkoxy, especially methoxy, group
Also preferred i8 the group of compounds of general formula (I~
wherein R4 is attached at the para-position relative to the amide
linkage
- , .
.. . .. ..
, ' . -
:. - : '
2~78~0~
SB320/C
- 4 _
Another preferred group of compounds of general formula (I) is
that wherein R4 is a halogen atom, especially a fluorine or chlorine
atom, or a hydroxy or C1_6alkoxy, especially methoxy, group.
A further preferred group of compounds of general formula (I)
is that wherein RS i~ a hydrogen atom.
- A yet further preferred group of compound of general formula
(I) is that wherein R7 is a C1_3alkyl, e~pecially methyl, group.
A particularly preferred compound of gen ral fon~ula (I) i~:
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-
l~ methyl-1,2,4-oxadiazol-3-yl)[l,l'-bipheny1]-4-carboxamide; and its
physio10gically acceptable salts and solvates.
other preferred compound~ of general forDula (I) include:
N-t4-methoxy-3-~(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4~-(3-
methyl-1,2,4-oxadiazol-5-yl)[1,1'-biphenyl]-4-carboxa~ide;
N- t 4-methoxy-3-(4-methyl-1-piperazinyljphenyl]-2'-methyl-4'-~5-
1 ~ ::
methyl-1,3,4-oxadiazol-2-yl)[l,l'-biphenyl]-4-c ~ nide;
N- t 4-methoxy-3-(4-methyl-1-piperaziny1)phenyl]-2'-methyl-5~-~5-
methyl-1,3,4-oxadiazol-2-yI)tl,l~-biphenyl]-4-carboxa~ide;
N-t4-methoxy-3-(4-methyl-1-piperaziny1)pheny1]-[4'-t5-
( thoxyr thyl)-1,2,4-oxadiazol-3-yl]-2'-methyl]t1,1'-biphenyl]-4-
carboxamide;
N- t 4-methoxy-3-(4-methyl-l_piperazinyl)phenyI]-2-methyl-4~-~5-
methyl-1,2,4-oxadiazol-3-yl)tl,l'-biphenyl]-4-carboxamide;
and their physiologically acceptable salts and solvates. ~
;~ 25 Further proferred compound~ of genoral formula ~I) include:
4'-t3-~Dimethylamino)-1,2,4-oxadiazol-5-y1]-N-l4-methoxy-3-~4-
methyl-l-pipoN zinyl)phenyl]-2'-methylt1,1'-biphenyl]-4-carboxa~ide;
N-t4-Methoxy-3-~4-methyl-1-piperazinyl)phenyl]-4'-~5-mothyl-1,2,4-
oxadiazol-3-yl)[1,1'-biphonyl]-4-carboxamide;
N-t4-~tothoxy-3-~4-mothyl-1-piporazinyl)phenyll-4'-~ othyl-l~-
1,2,3-triazol-4-yl)t1,1'-biphonyll-4-car~oxamide;
N-t4-Hethoxy~3-~4-methyl-1-piporazinyl)phonyll-2'-methyl-4'-tt5-
~methylsulphonyl)methyl]-1,2,4-oxadiazol-3-yl]~ -biphenyl]-4-
carboxamide;
N-[4-Methoxy-3-~4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-
methyl-1,3,4-thiadiazol-2-yl)~l,l'-biphenyl]-4-carboxa~ide;
.
.
.. ~ . , .
-
785~
Ss320/c
-- 5 --
4'-[5-(Hydroxymethyl)-1,2,4-oxadiazol-3-yl]-N-t4-methoxy-3-(4-
methyl-l-piperazinyl)phenyl]-2'-methyl[1,1'-biphenyl]-4-carboxa~ide;
and their phy~iologically acceptable salts and ~olvates.
Particularly preferred compounds of general formula (I)
include:
N-[4-Chloro-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-
methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamide;
N-~4-Hethoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(3-
methyl-1,2,4-thiadiazol-5-yl)[1,1'-biphenyl]-4-carboxa~ide;
2'-Chloro-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4'-(5-
mothyl-l~3~4-oxadiazol-2-yl)[~ -biphenyl]-4-carboxamide;
N-[4-Hethoxy-3-(4-methyl-1-piperazinyljphenyl]-2'-methyl-4'-(1~2,3-
thiadiazol-4-yl)[1,1~-biphenyll-4-carboxa~ide;
2'-Methyl-N-[4-methyl-3-(4-methyl-1-piperazinyl)phenyI]-4~-(5-
methyl-1,3,4-oxadiazol-2-yl)[l,l'-biphenyl]-4-carboxanide;
~5 4~-(1,5-Dimethyl-18-1,2,4-triazol-3-yl)-N-~4- ehoxy-3-(4-mothyl-1-
piperazinyl)phenyl]-2'-mothyl[1,1'-biphenyll-4-carboxanide;
2-chloro-N-[4-methoxy-3-(4-methyl-l-piperazinyllphonyl]-4~-(5
; ~ethyl-1,2,4-oxadiazol-3-yl)[1,}'-biphenyll-4-carboxa~ide;
N-~2-Fluoro-4-methoxy-5-(4-methyl-1-piperazinyl)phenyl]-2-methyl-4'-
~5-mothyl-1,2,4-oxadiazol-3-yll[l,l'-biphenyl]-4-carboxamido;
N-~4-Chloro-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-
- mothyl-1,3,4-oxadiazo1-2-yl)tl,l'-biph-nyl]-4-carboxamidei
N-~4-sromo-3-(4 _ thyl-1-piperazinyl)phenyl]-2'methyl-4'-15-methyl-
1,2,4-oxadiazol-3-yl][l,l'-biphonyl]-4-carboxamido;
N-14-Hothoxy-3-(4-mothyl-1-piperazinyl]-2'-methyl-4'-(1,3,4-
oxadiazol-2-yl)[l,l~-biphenyl]-4-carboxamido;
and their physiologically acceptable sa}ts and solvate~.
5-8ydroxytrypta~ine (~erotonin) is a neurotran-mittor which i8
widoly di~tributod within tho contral norvou~ y-tom (CN8),
30 plat-lots and tho ga~trointo~tlnal tract. Chango~ in!tran~mi~sion in
serotonergic pathways in the CNS are known to modify, for oxample,
mood, psychomotor activity, appetite, memory and blood pressure.
Release of 5-hydroxytryptamine from platelets can mediate vasospasm
while changes in free 5-hydroxytryptamine levels in the
gastrointestinal tract can modify secretion and motility.
SB320/C - 6 - 2 0 7 8 5 0 5
Abundant pharmacological studies have led to the discovery of
multiple types of receptors for 5-hydroxytryptamine, thus providing
a molecular basis to the diversity of its actions. These receptors
are classed as 5-HTl, 5-HT2 and 5-HT3, with 5-HTl receptors being
sub-classified as 5-HTlA, 5-HT1B, 5-HT1C, 5-HTlD and 5-HTlD(like)
receptors. The identification of these classes and sub-classes of
receptor i~ based mainly on radiological binding studies.
Compounds having a selective antagonist action at 5-HTlD
receptors such as those described herein may exhibit a beneficial
effect on subjects sufferiDg from CNS disorders.
Accordingly, in a further aspect of the present invention,
there is provided a method of treating a patient suffering from a
CNS disorder, which method compri~es administering to tho patient an
effective amount of a 5-HT1D antagonist. Th- patient is preferably
a human patient.
In anoth r aspect of the present invention, there i8 provided a
5-HTlD antagonist for use in th manufacture of a medicament for the
treatment of a CNS disorder.
In the present specification, a 5-~T1D antagonist is a non-
naturally occurring (synthetic) compound that specifically and
selectively antagonises 5-HTlD receptors, i.e. - b10cks the
specific actions of 5-hydroxytryptamine _ diated by the 5-HTlD
receptor. Such compounds may be identified by a high level of
affinity (pRi 2 8) in the in vitro human cortex and`guinea-pig
striatum radioligand binding assays described by Hoyer et al,
Neuroscience Letters, 1988, 85, p357-362. Activity at 5-HT1D
receptors may be confirmed~in vivo~using the guinea pig rotation
model de~cribed by G A Higgins et al, Br. J. Pharmacol., 1991, 102,
P305-3io.
A 5-HTlD antagoni~t for uso in tho pro-ent method of troatment
mu~t bo ~loctivo for 5-HT1D roceptor~. In the pre~ont
specification, this means that the 5-HTlD antagonist must be 30 or
more times ~ore ~elective for 5-HTlD receptors than 5-HT1A, 5-HT1C
or 5-HT2 receptors.
According to this definition the affinity of a compound for 5-
HT1A, 5-HT1C and/or 5-HT2 receptors is measured using the in vitro
tests described in the following publications:
' ' ,
ss320/c h ~ ~ ~ 5 0 ~
-- 7 --
5-HTlA Gozlan et al, Nature, 1983, 305, pl40-142
5-HTlC Pazos et al, Eur. J.Phar~acol., lg84, 106, p531-538
5-HT2 Humphrey et al, Br. J. Pharmacol, 1988, 94, pll23-1132
(rabbit aorta modell.
Thus, for exa~ple, compounds of the present invention have been
shown to inhibit 5-hydroxytryptamine induced contraction of the dog
isolated saphenous vein and to antagonise tbe 5-hydroxytryptamine
induced inhibition of neurotransmission in central and peripheral
neurones.
5-HTlD Antagonist~, and in particular the compounds of the
pre~ent invention, may therefore be of use in the treatment of CNS
disorders such a~ mood disorders, including depression, ~easonal
affective disorder and dysthymia; anxiety disorders, including
generalised anxiety, panic disorder, agoraphobia, social phobia,
obsessive compulsive disorder and post-traumatic stress disorder;
memory disorders, including dementia, a~nestic disorders and age-
associated memory impairment; and disorders of eating behaviour,
including anorexia nervosa and bulimia nervosa. other CNS
disorders include Parkinson's disease, dementia in Parkinson's
disea~e, neuroleptic-induced parkin~onism and tardive dy~kinesias,
as well as other psychiatric di~orders.
5-HTlD Antagonists, and in particular compounds of the present
invention, may also be of use in the treatment of endocrine
disorders such as hyperprolactinaemia, the treatment of va~ospasm
(particularly in the cerebral vasculature) and hypertension, as well
as disorders in the gastrointestinal tract where changes in motility
and secretion are involved. They may also be of use in the
treatment of sexuAl dysfunction.
Therefore, according to a second aspect of the invention, we
provide a compound of general formula ~I) or a physiologically
acceptable salt or solvate thereof for use in therapy.
According to a further aspect of the present invention, we
provide a compound of general formula (I) or a physiologically
acceptable salt or ~olvate thereof for use in the treatment of the
aforementioned disorders.
.
ss320/c 2 0 7 ~ ~ O ~
-- 8 --
According to another aspect of the invention, we pro-ride the
use of a compound of general formula ~I) or a physiologically
acceptable salt or solvate thcreof for the manufacture of a
therapeutic agent for the treatment of the aforementioned disorders.
According to a further aspect of the invention, we provide, a
method of treating the aforementioned disorders which comprises
administering an effective amount to a patent in need of such
treatment of a co~pound of general fo~ula (I) or a physiologically
acceptable salt or solvate thereof.
In particolar, according to another aspect of the invention, we
provide a compound of general formula (I) or a physiologically
acccptable salt or solvate thereof for use in the treatment or
prophylaxis of depression.
It will be appreciated that the compounds according to the
invention may advantageously be used in conjunction with one or more
15 other therapeutic agents, for instanco, different antidepressant
agents such as tricyclic antidepressants (e.g. amitriptyline,
dothiepin, doxepin, trimipramine, butriptyline, clomipra~ine,
desipramine, imipramine, iprindole, lofepramine, nortriptyline or
protriptyline), mono~ine oxidase inhibitors (e.g. isocarboxazid,
phenelzine or tranylcyclopramine) or 5-HT reuptake inhibitors (e.g.
fluvoxamine, sertraline, fluoxetine or paroxetine), and/or
antiparkinsonian agents such as dopa~inergic antiparkinsonian agents
(e.g. levodopa, preferably in combination with a peripheral
decarboxylase inhibitor e.g. bonserazide or carbidopa, or a dopamine
agonist e.g. bromocriptine, lysuride or pergolide). Tt is to be
understood that the present invention cov-r- the use of a compound
of general formula ~I) or a physiologically accoptable salt or
solvate the~roof in combination with one or mor- othor thorapoutic
agents.
Thus there is provided in a further or alternative aspect of
the present invention a compound of general formula ~I) or a
physiologically acceptable salt or solvate thereof and an
antidepressant agent in the presence of each other in the human or
non-human animal body for use in the treatment of the aforementioned
disorders.
i` s~320~c 207~0~
In a particular aspect of the present invention there is
provided a compound of general formula (I) or a physiologically
acceptable salt or solvate thereof and an antiparkinsonian agent
such as a dopaminergic antiparkinsonian agent, e.g. levodopa, and a
S peripheral decarboxylase inhibitor, e.g. benserazide or carbidopa,
or a dopa~ine agonist e.g. bromocriptine, lysuride or pergolido in
the presence of each other in the human or non-human animal body for
use in the treatment of Parkinson's disease, dementia in
parkinsonism, neuroleptic induced parkinsonism and tardive
dyskinesias.
~ In using a compound of general formula ~I) or a physiologically
acceptable salt or solvate thereof ahd one or ~ore therapeutic
agents it may be preferable to employ the actlw ingredienes in the
for~ of #eparate pharmaceutical formulations. A combined
formulation can be used, however, in such a combined formulation the
active ingredient- must of course b stable and mutually compatible
in the particular formulation e~ployed.
It will be appreciated that administration of the active
ingredients to a human or non-human patient;~ay be si ultaneous,
separate or sequential. Where administration is not simultaneous,
the delay in administering the second of the active ingredients
#hould not be #uch a# to lose the ben-ficial effect of the
- combination.~ ~ ~
While it i# pos~ible that a coDpound of general formùla (I) may
2S be administered a8 the raw chemica} it is preferable to present the
active ingredient as a pharmaceutical formulation.
The compounds of general formula ~I) and their physiologically
acceptable salts and solvate# may bo formulatod for administration
in any conveniont way, and tho invontion thoroforo al-o includes
within its copo phar~aceutioal oompo-ition- oomprising at lea-t one
30 ~oompound of genoral formula (I) or a physiologioally aooeptable salt
or solvate thereof. Such compositions may be presented for use in a
conventional manner in admixture with one or more physiologically
acceptable carriers or excipients.
The carrier(s) must be ~acceptable~ in the ~en#e of being
compatible with the other ingredients of the formulation and not
deleterious to th- recipient thereof.
,~ "
. .
. .
-
i
- ~078~
SB320/C
-- 10 ~
Thus, the compositions according to the invention may be
formulated for oral, buccal, parenteral or rectal admunistration or
in a form suitable for administration by inhalation or insufflation.
oral administration is preferred.
Tablets and capsules for oral administration may contain
conventional excipients such as binding agents, for example, syrup,
acacia, gelatin, sorbitol, tragacanth, mucilage of starch or
polyvinylpyrrolidone; filler-, for exaaple, lactose, sugar,
aicrocrystalline cellulose aaize-stareh, calcium phosphate or
sorbitol; lubricants, for example, aagnesium stearate, stearic acid,
talc, polyethylene glyeol or siliea; disintegrnnts,~for exa~ple,
potato stareh or sodium starch gIyeollate; or wetting agents sueh as
sodium lauryl sulphate. The tablets may be eoated according to
methods well known in the art. Oral liquid preparations may be in
the form of, for ex~mple, aqu-ous or oily suspeD~ions, solutions,
emulsioDs, ~yrups or elixirs, or aay be presented ns a dry product
for constitution with water or other ~uitable vohicle bofore use.
Such liquid preparations may contain conventional additives such as
uspending agents, for exaaple, sorbitol syrup, methylcellulo~e,
glucose/sugar syrup, gelatin, hydroxypropyl methylcellulose,
carboxy~ethylcellulose, aluminiua stearate gel or hydrogenated
~ edible fats;~emulsifying agents, for example, lecithin, sorbitan
; mono-oleate~or acacia; non-aqueou- vehicles (whicb may include
edible oils), for example, almond oil, fractionated coconut oil,
oily esters, pr~pylene glycol or ethyl aleohol; and preservatives,
for example, methyl~or propyl ~-hydroxybenzoates or sorbic acid.
The compo~itions may also be formulated as suppositories, e.g.
containing conventional suppository bases sueh as eoeoa butter or
other glycerides.
For buecal administration the co~po-ition may tako tho for~ of
tablets or lozongos fon~ulated in eonvontional mannor.
The composition according to the invention aay be fo~mulated
for parenteral administration by bolus injection or continuous
infusion. Formulations for injection may be presented in unit dose
form in ampoules, or in multi-dose containers with an added
preservative. The compositions may take such fonms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may contain
-; ' ,' '
: ~;'
SB320/C ~ 7 8 ~ 0 5
formulatory agents such as ~uspending, stabilising and/or dispersing
agents. Alternatively the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g. sterile, pyrogen-free
water, before use.
For administration by inhalation either orally or nasally the
compositions according to the invention are conveniently delivered
in the form of an aerosol spray presentation from pressurised packs
with the use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
other suitable gas, or from a nebuliser. In the case of a
pressurised aerosol the dosage unit may be d-ternined by providing a
valve to deliver a metered amount.
Altern-tively, for~ admini-tration by inhalation the
composition~ according to the invention ~ay take the form of a dry
powder co~position, for example a powder mix~of th compound and a
suitable powder base such as lactose or starch. The powder
compo~ition may be presented in unit dosage form in, for oxample,
capsules or cartridges of o.g. gelatin, or blister packs fro~ which
tho powder may be administered with the aid of an inhaler or
insufflator. ~
The pharmaceutical formulations according to the invention may
also contain other active ingredients such as antimicrobial agents,
~ or preservatives. ~ ~
-`~ The compositions accordlng to the invention~may be prepared by
~ixing the various ingredients using conventional mea~s.
It will be appreci ted that the amount of a compound of general
formula (I) réquired for use in treatment will vary not only with
the particular compound selectod but also with tho routo of
administration, th- naturo of tho conditlon b-lng troat-d and tho
ag- and condition of the pati-nt and will ultimately be at tho
30 discretion of the attendant physician or veterinarian. In genoral,
however, a proposed dose of the compounds of the invention for
administration in man is 0.5 to lOOOmg, preferably 1 to 200mg of the
active ingredient per unit dose which could be administered, for
example, 1 to 4 times per day.
The compounds of the invention may be prepared by a number of
processes as described in the folIowing. In describing *he
. .
,
' ,'' -, '' ::
. .
- . - ~
SB320/C - 12 - ~ ~ 7 8 ~ ~ ~
processes which may be used for preparing the compounds of general
formula (I) or intermediates useful in the preparation thereof, any
o Rl-Rll, Z, and k in the various formulae are as defined in
general formula (I) unless otherwise stated.
It will be appreciated that in the following methods for the
preparation of compounds of general formula (I), for certain
reaction steps it may be necessary to protect various reactive
substituents in the starting materials for a particular reaction and
subsequently to re~ove the protecting group. Such protection and
subseguent deprotection may be particularly pertinent where R7, R8,
R9 and/or R10 in intermediates used to prepare compounds of general
- formula (I) are hydrogen atoms. Standard protection and
deprotection procedures can be employed, for example formation of a
phthalimide (in the case of a primary amine), benzyl, trityl,
benzyloxycarbonyl or trichloroethoxycarbonyl derivatives.
Subsequent removal of the protecting group is achieved by
conventional procedures. Thus a phthalimide group may be removed by
treatment with hydrazine or a primary amine, for example
methylamine. Benzyl or benzyloxycarbonyl groups may be removed by
hydrogenolysis in the presence Or a catalyse e.g. palladium, and
trichloroethoxycarbonyl derivatives ay be removed by treatment with
zinc dust. Trityl groups may be removed under acidic conditions
using standard procedures.
It may also be necessary in some cases to protect carboxylic
25 acid groups (e.g. as esters) or aldehyde or ketone groups (e.g. as
acyclic or cyclic acetals or ketals or as thioacetals or
thioketals). Subsequent removal of these protecting groups is
achieved by conventional procedures. Thus for example alkyl esters
may be removod under conditions of acidic or ba-ic hydroly~is,
bonzyl osters may bo romovod by hydrogonolysis in the prosenco of a
30 catalyst e.g. palladium. Acyclic or cyclic acetals or ketals may be
removed under conditions of acidic hydrolysis and thioacetals and
thioketals may be removed using a mercuric salt.
Hydroxyl groups may also need protection and these may be
adeguately protec~ed under amenable conditions as their esters or
trialkylsilyl, tetrahydropyran and benzyl ethers. Such derivatives
may be deprotected by standard procedures.
~-~ SB320/C -- 13 -- 2 () 7 8 5 ~ ~
According to Qne general process (1), the compounds of general
formula (I) may be prepared by a carbonylation reaction involving an
aniline (II)
R3
S ~ .
H2N~
~R4 al)
R
(where R3, R4 and RS are as defined in general formula (I)) and a
halopenyl compound (III~
~Y (111)
R2
~ where Y represents a halogen ato~ e.g. broDin- or iodine or the
~group -OSo2CF3, and Rl and R2 are as d-fined in general formula
(I)).
The reaction takes plaoe, for example, in the presence of
20 carbon monoxide using a palladiun salt as a catalyst. The reaction
is effected in the presence of a suitable base e.g. a trialkyla~ine
wch a- triethyla~ine or tri-n-butylamine and may be conducted~ln a
suitable solvent such as an~amide e.g. dimethylformamide or a
nitrile eg aoetonitrile at a temperature within the range of -10C
25 to +150C.
Suitable palladium salts for the reaction include
t ria rylp ho 8p hine p a ll a diu m ( I I) s alt 8 suc h as
bis(triphenylehosebine)ealladium (II) chloride.
According to anothor gon-r-l proco~- (2), tho compound~ of
gen-ral formula ~I) may bo proparod by tsoating a compound of
30 formula (IV)
Rl . .
R 2~00NH ~ ~
.
~ ,.';: . ~ .. ~' .-
~ S8320/C 2~78~
- 14 -
with an a~ine dihalide of for~ula (v)
R7N(CH2C82Hal)2 (V)
(where Hal i8 a chlorine, bro~ine or iodine atom).
The reaction may conveniently take place in the presence of a
polar ~olvent such as an alcohol (e.g. n-butanol) or a nitrile ~e.g
acetonitrile), optionally in the pre~ence of a ba-e, for exa~ple, an
alkali metal carbonate uch aa odium carbonate or pota-sium
carbonate, or alternatively in a non-polar olvent (e.g.
chlorobeozene) in the absence of a base. The reactions may
conveniently be carried out at an elevated temperature, for example,
reflux.
According to another general process (3), the compound- of
general formula (I) may be prepared by reacting an aniline of
formula (II) with an activated carboxylic acid derivative of formula
R
~where L i8 a leaving group~).
Suitable activated carboxylic acid derivatives repre~ented in
formula (VI) include acyl halide- (e.g. acid chloride-) and acid
anhydrides including mixed anhydride- (e.g. acid formic anhydride).
These activated derivatives may be formed from the corresponding
acid of for~ula (VII)
~! 30 ! ~--C2 H (Vll)
R
by well known procedures. For example, acid chlorides may be
prepared by reaction with phosphorus pentachloride, thionyl ch~oride
or oxalyl chloride and acid anhydrides may be prepared by reaction
.
~~ s~20/c 2078~0~
- 15 -
with an appropriate acid anhydride (e.g. trifluoroacetic anhydride),
an acid chloride (e.g. acetyl chloride), an alkyl or aralkyl
haloformate (e.g. ethyl or benzyl chloroformate) or methanesulphonyl
chloride.
S Activated carboxylic acid derivatives of formula (VI) may al~o
be prepared in situ by the reaction of the corresponding acids of
formula (VII), with a coupling reagent such as carbonyldiimidazole,
dicyclohexylcarbodiioide or diphenylphosphorylazide.
The conditions under whieh the activated earboxylie acid
derivatives of formula ~VI) are formed and subseguently reaeted with
the anilines of formula (II) will depend upon th`e nature of the
activated derivative. ~owever, in general the reaction between the
compounds (II) and (VI) may be carried~out in a non-aqueous mediuD
.
sucb as, for example, dimethylforma~ide, tetrahydrofuran,
acetonitrile or a halohydroearbon sueh as dichloromethane at a
temperature within the range -25C to ~150C. The reaetion may
optionaIly be ¢arried out in the presenee of a base such as
triethylamine or pyridine and the base may also be used as the
solvent for reaction.
Where acid ehlorides are used, th- r-aetion may be carried out
using the Schotten-Baumann technique in the presence of a suitable
base, for examp`le, gueous sodium hydroxide, conveniently at a
temperature between 0C and 100C, for example, roo~ temperature.
According to another general process (4a), the compounds of
general formula (I) may be prepared by treating a compound of
formula ~VIIIa)
RI
I ~ R
~ OONH ~ ~VI~)
(where Y represents a bromine or iodine atom or the group -0502CF3)
with a compound of formula (IXa)
R2B(0H)2 ,(IXa)
or an ester or an anhydride thereof.
- ~
`.::
SB320/C - 16 - ~G7~0~
Alternatively, according to the general process t4b), the
compounds of general formula (I) may be prepared by treating a
compound of formula (VIIIb)
Rl
5~ ~ R
(OH~2 ~ ~ R 4
or an ester or an anhydride thereof, with a compound of formula
R -Y (IXb)
where Y represents a bromine or iodine atom or the group -0502CF3.
15Both reactions may be effected in the pre~ence of a transition
metal catalyst such as (Ph3P)4Pd (where Ph represents phenyl) in a
~uitable ~olvent such as an ether (eg 1,2-dimethoxyethane or
tetrahydrofuran) in the presence or absence of water, or an aromatic
hydrocarbon (eg benzene). The reaction is preferably carried out in
the presenco of a base such as an alkali or alkaline earth metal
carbonate (eg sodium carbonate) at a suitable temperature up to
reflux.
Compounds of general formula (I) in which R2, R4 and R5 have a
particular meaning may be converted into another compound of the
invention by standard methods of interconversion.
For instance, when R2 contains a hydroxy or alkoxy group and/or
when R4 and~or R5 represents hydroxy or alkoxy these groups may be
interchanged by standard methods of 0-alkylation or o-dealkylation.
Thus, for example, a compound in which R4 ropresents hydroxy m~y be
prepared by treating a correspond$ng compount in which R4 reprosents
30 metho~y wlth a reagent syst~m capable of removing the methyl group
e.g. a mercaptide such as sodium ethylmercaptide in a solvent such
as dimethylformamide, lithium iodide in collidine, boron tribromide
in a halohydrocarbon solvent e.g. methylene chloride or molten
pyridine hydroch,loride.
Intermediates of formula (II) may be prepared from the
corresponding compound of formula ~X)
2078~05
~ ~ s~320/c
17
I`H 2
02N~
~ R' oK)
by reaction with a compound of formula (XI)
~ 7
N _ R
~2C~
10 ' ~ :
in the presence of aoetic anhydride, followed by reduction of the
di~etopiperazine intermediate thus formed using, for~example borane.
The reaction may~be carried out at a temperature between 50C and
refIux, and optionally in a solvent such as an ether, e.g.
tetrahydrofuran, or toluene. The nitro group may be subsequontly
converted into an amine using standard methodology.
Alternatively, intermediates of formula (II) in which R4 is
adjaceot to R3, and RS is a hydrogen atom, may be prepared by
nitration of a compound of formula (XII)
R
< ~
R'
using an appropriate nitrating system such as sulphuric acid and
potagsium nitrat-, or nitroniu~ tetrafluoroborate, in the pres~nce
~ of a solvent, for example, acotonitrile, or altornatively, whoro R7
;~ is not a hydrogen atom, by nitro-ation usinq, for oxa~plo, sodium
nitrite and a ~uitable acid uch a~ sulphuric acid in a solvent, for
example, water, followed inleach ca~e by reduction of tho nitro or
nitroso group using standard methodology.
Intermediates of formula (IV) may be prepared by reduction of
the corre~ponding mtro co pound of general formula ~XIII)
' ~ ~
-
:
~ .' ' ~ - , - .
207~0~
~ SB320/C
R ~ 18 - ~o2
~-CONH~ (Xlll)
R R R4
The reduction may be effected by catalytic hydrogenation using
a metal cataly~t such as palladium or platinum or oxides thereof,
preferably, in a solvent such a~ an alcohol e.g ethanol, or
;0 alternatively by using Raney nickel and hydrazine in a solvent such
as an alcohol e.g. ethanol.
Intermediates of formula (XIII) may be prepared by condensing a
compound of formula (VI) with a compound of formula (X) under the
conditions of general proce~ (3).
It will be appreciated that, where necessary, a halogen
sub~tituent may be converted into a carboxyl group using standard
methodology thus, for exa~ple, intermediates of formula (VII) may
be prepared from an intermediate of formula (III) by lithiation
- using, for example, n-butyl lithium followed by guenching with
carbon dioxide.
Intermediates of formula (VIIIa) and (VIIIb) may be prepared by
reaction of a compound of formula (II) with a compound of formula
(XIVa) or (XIVb), respectively,
Rl R
~ COL ~KrVa) ~ L ~KIVb)
(H)2B
according to the method of genoral proces0 (3).
The boronic aoid intermediates of $ormulao ~VIIIb), (IXa) and
(XIVb) or their ostors or anhydrides may be used inlsitu under the
condition~ described above for general process (4).
Intermediates of formula (VII) may be prepared by the reaction
of a compound of formula (IXa) or (IXb) with a compound
corresponding formula (XIVa) or (XIVb) in which L represents a
hydroxy group, respectively, according to the method of general
process (4).
.
~\
207850~
SB320/C
-- 19 --
Intermediates of formula (II) may also be prepared from the
corresponding carboxylic acid using conventional procedures (e g by
Curtius rearrangement)
Intermediates of formulae (V), (X), (XI), (XII), (XIVa) and
S (XIVb) are either known compounds or may be prepared by standard
methodology or methods analogous to those desaribed herein
Intermediates containing the group R2 may be prepared by
methods described herein and usinq technigues well known in the art,
such as thos- described in "Compreh nsive 0rganic Chemistry", Vol 4
I() by D Barton and W D Ollis, Pergamon Press, Oxford ( 1979) ~see
especially pages 1020-1050 for fiv--membered mixed heteroatom ring
syst_) or in "Compreh-nsive Heterocyclis Chem~stry", Vol 6 by A R
Katritzky and C W Rees, Pergamon Press, Oxford ~1984) ~ee pagé8
365-577) .
Physiologically acceptable acid addition salts of the coDpounds
of g-neral formula (I) I ay be pr-pared by treating the corresponding
free base with a witabl- acid using conventional methods Thus,
'~ for xample, a g-n-rally conveni-nt method of forming th- acid
addition salts is to mix appropriate guantiti-s of the fr-e bas- and
20 tho acid in an appropriat- solvent g an alcohol such a~ ethanol or
an ester such as thyl ac-tat-
Salts of compounds of general formula (I) may also be converted
to differene physiologically accepeable salts of~ compounds of
general formula (I) using conventional methods
The invention is illustrated but not limieed by the following
exaniples in which temperatures are in C Thin layer chromatography
(t l' c ) was carri-d out on silica plates
The following abbreviations are used -
DMP - di~cthylf orl~amid-; T15A - triethylamino; HMPA
hoxaa-thylpho-phoramido; THF - totrahydrofuran; MSC -
30 methanollulphonyl chloride; 8TPC - bis~triphonylph0sphine)palladium
~II) chloride; DMA - dimethylamine; IMS - industrial methylated
spirits; SPC - Short path chromatography carried out on silica
(Merck 7747 ) unless otherwise stated FCC - Flash column
chromatography carried out on silica (Merck 9385). 'Dried~ refers to
drying using sodium sulphate or magnesium sulphate unless otherwise
stated
- . ~
.
:
:
~07~5~
--- s~320/c
- 20 -
The following solvent systems were used:-
System A - dichloromethane:ethanol:0.88 ammonia; System B -
dichloromethane:methanol:0.88 ammonia.
Intermediate 1
3-(4-Bromo-3-methvlPhenYl)-5-methYl-1,2,4-oxadiazole
A solution of sodium methoxide (1.93q) in methanol (15ml) was added
dropwise over 10 min to a solutioD of hydroxylamine hydrochloride
(2.48g) in methanol (30ml). The mlxture was stirred for Ih at 20
0 and was then filtered. 4-Bromo-3-methylbenzonitrile (7g) was then
added to the filtrate, and the mixture heated to reflux for 18h.
The ~olvent wa~ then evaporated giving a grey solid, a portion of
which (2.2g) wa3 dissolved in acetic anhydride (6ml) and heated to
80 for 18h. The reaction was cooled aDd was poured into water
(lOOml). The solid was separ ted, colleoted and recryotallised from
i-opropanol (20ml) giving tho title comPound as colourless
Dicrocrystal~ (896mg) m.p. 78.
'
Inter~ediato 2
5-(4-Bromo-3-methvlDhenYl)-3-thYl-1,2,4-oxadiazole
Sodium metal (602mg) was added to a su~pension of molecular sieves
(4A) in absolute ethanol (30~1) under nitrogen at 20. After l5min
N-hydroxyethanimidamide (1.94g) was added. Stirring was maintained
for lh whereupon Intermediate 8 (lg) was addod. The nixture was
heatod to reflux for 1.5h, then filtered and the filtrate evaporated
to dryness. The residue was dissolved in water (75ml) and extracted
with ethyl acetate (2x75ml) and the dried extracts evaporated to
give the title oomPound as a colourless solid (856mg) m.p. 75-77.
Intermediato 3
30 Heth~1_4-methoxY-3-(4-methvl-1-Piperazinvl)benzoate hvdrochloride
A su~pension of 2-chloro-N-(2-chloroethyl)-N-methylethanamine
hydrochloride (1.92g) and methyl 3-amino-4-methoxybenzoate (1.81g)
in n-butanol wa~ refluxed with stirring for 19h. Anhydrous sodium
carbonate (0.54g) was added and refluxing continued for 8.5h. The
solvent was then removed to give an oil which was taken up in water
(50ml) and 2N hydrochloric acid (50ml) and extracted with ethyl
` ' ', .
'. .~.
~7~0~
SB320/C
- 21 -
acetate (2x50ml). The acid solution wa~ then basified with sodium
bicarbonate and re-extracted with ethyl acetate ~3x50ml). The
extracts were dried and concentrated to a semi-solid ~2.47g) which
was absorbed Srom sygtem A (200:8:1) ~5ml) onto Rieselgel G ~100g).
~lution with the same solvent gave starting material and minor basic
impurities. Further elution with System A ~100:8:1) (450ml) gave
firot minor impurities and later fractions afforded the free base of
the desired produot as a gum (0.48g). This was taken up in methanol
(Sml), filtered and treated with ethereal hydrogen chloride and
d luted to 25ml with ethyl acetate.~ A cream coloured solid
separated, was filtered and the solid (0.586g) recrystallised from
~ethanol:ethyl acetate to give the title co ound ~.p. 202-204C.
' :
Intermediate 4
4-~ethox -3-l4-methyl-1-Pl~erazinYl)ben-oio acid hYdrazide
Th- free base of Intermodiate 3 (2g) in methanol (20ml) was treated
with hydrazine hydrate (4d ) and refluxed under nitrogen for 16h.
The solution was evaporated and then adsorbed fron ethanol onto
sillca g l l~erck Art. 7734, 5g]. Purlfication by SPC eluting with
System A ~91:9:0.9) gavo the title comDound as an off-white solid
~0.764g)-
T.l.c. System A ~90:10:0.1), Rf 0.2.
Intermediate 5
4-M thoxv-3-14 _ thvl-l-DiPerazinyl)benzenamin
A solution of~Intermediate 4 ~0.739) in water ~30~1) was mixed with
condentrated hydroohloric acid ~0.6ml)~, the solution cooled to O to
5 4 nd a solution of sod~u~ nitrite (0.219g) in water (lOml) added
during 5min.~ The solution wa- tirred at 0-5C for 20min, thon lh
at 23C, and troated with conc-ntratod hydrochloric acid (40ml) and
acetic acid (40ml). Tho mixturo was heatod at roflux for 2h, cooled
a~d poured into aqueous sodium hydroxide (5N; 260ml). The mixture
was extracted with ethyl acetate (3x500ml), and the combined, dried
organic extracts were evaporated to give the title comDound as a gum
(0.19Og).
T.l.c. Sy~tem A (95:5:0.5), Rf 0.2.
..
.' '
.
~' ~
: .
. .
~078~0~
sB32o/c
- 22 -
Inter~ediate 5 was also made by the alternative two-~tep reaction a~
follows:-
(a) l-Methvl-4-(2-methoxv-S-nitro~henvl)~iDerazine
1-(2-Methoxyphenyl)-4-methylpiperazine (5.36g) was acidified with 5N
sulphuric acid and the excess water evaporated in vacuo.
Concentrated sulphuric acid (95-98~, 22ml) was added and the mixture
stirred at room temperature until ho~ogeneous. To the stirred, dark
solution was added portionwise at roo~ temperature potassium nitrate
l (3.07g) in ten portions at intervals of approximately Smin. The
mixture wa~ stirred at room temperature for 4h then poured onto ice
(-500ml) and the mixture made slight~y alkaline with anhydrous
sodium carbonate. The basic mixture was extracted with ethyl
acetate (4xl50ml) and the combined extracts dried. After Ih the
S ~ixture was filtered and the filtrate evaporated to dryness in
vacuo. The dark red residue was diluted with ether (200ml) and the
solid which ~eparated ~0.51g) was filtered off and discarded. The
filtrate was evaporated to dryne~s and the oily residue mixed with
other (300ml) and the suspension filterod. The filtrate was
evaporated to dryness to give-a red gum which very slowly olidified
to give the title comDound (5.45g)
T.l.c Syste~ A (150:8:1), Rf 0.45
(b) 4-Methoxv-3-(4-methYl-l-DiDerazinvl)benzeneamine
To a solution of the product of step (a) (5.07g) in ethanol (70ml)
was added a paste of Raney Nickel in water (2g). To the warmed
suspension was added, with constant agitation, hydrazine hydrate
(SD1) dropwise during 20min with occasional warminq. Aftor tho ~ain
cfforvescenco had cea-od, tho ~u-pon-ion wa- hoatod for 15min and
then filtored with tho aid of othanol undor nitrogon. Tho residues
! 1 30 were kept moi~t and washed with othano} and the combined filtrate
and washings were evaporated to dryne~s with the aid of ethanol.
The dark residue wa~ re-evaporated with ethanol (20ml), resuspended
in ether (40ml) and the mixture filtered. The re3idue was washed
with ether and dried to give a ~olid consisting of the title
compound ~2.365g)
T.l.c system A (70:8:1), Rf 0.25.
2~78~Q~
SB320/C
- 23 -
Intermediate 6
.
4-Bromo-N-r4-methoxv-3-(4-methYl-l-DiperazinYl)DhenYllbenzamide
.
A solution of Inter~ediate 5 (0.1689) in pyridine (3ml) was treated
with 4-broaobenzoyl chIoride ~0.25g) and stirred at 110, under
nitrogen, for 5h. Sodium bicarbonate (20ml; 8%) was~added and the
mixture was evaporated. The residue wa~ pre-adsorbed onto silica
gel ~Merck Art. 7734 ca.; 5q] and purified by SPC eluting with Sy~te~
a (97:3:0.3) to give the title com4ound as a beige solid (0.237g),
Dl p. 158.5-159.5C-
Intermediate 7
~4-r r [4-MethOXy-3-(4-methyl-l-piperazinyl)Dhenyllanlinolcarbonyll
DhenYllboronic acid
n-8utyllithiu~ (7.5al of 1.6M solution in hexane) was added dropwise
at -90 to -100 to a stirred solution of Intermodiate 6 (404ag) and
triisopropylboraté~2.77al) in dry THF (20~1) over ~5~in undor
nitrogen, and ~tirring continued for 1.5h at -90 to -103 for 1.5h.
After 3h at -78, the cooling bath was reaovod and th- aixture
stirred at ~23 for llh. Nat (4ml) was added, and, after lh, the
mixturo was vaporated. The resldue was adsorbed froa Systea A
(50:45:5) onto silica gel (Merck 7734, lOml) and purified by FCC
eluting with Systea A (89slO:1 ~ 50:45:5) to giYe firstly recov-red
impure starting material followed by the title comDound as a cr-am
2S foam (280mg)
T.l.c. Syste~ A ~50:45:5) Rf 0.04
: : :
Intermediate 8
MethYl 4-bro-3~-~thYlbenzoate
4-Bro~o-3-~ethylbenzoic acid ~lOg) wa~ su~pond-d in methanol (50ml)
30 containing conc. sulphuric aoid ~2ml). Th- mixture was heat-d to
reflux for 18h. On addition of 8~ NaHC03 ~lOOml) to the cooled
reaction, a solid was for~ed which was collected by filtration.
Drying in vacuo at 40-45- gave th- title comDound as a liquid which
recrystallised on cooling (10.25g) m.p. 39.5-40.5-C
nter~ediate 9
.
.
.,
.. .
.~ .
. , ~ . ..
--``` S8320/C ~G7g~0~
- 24 -
4-Bromo-3-methvlbenzoic acid hydrazide
A solution of Intermediate 8 (2g) in methanol (20ml) containing
hydrazine hydrate (l.lml) was heated to reflux for 18h. On cooling
a solid crystallised which was collected by filtration and washed
with ether to give the title com~ound a~ colourless needles (1.81q),
m.p. 164-166-C.
Intermediate 10
2-~4-Bromo-3-methvl~henYl~-5-methYl-1,3,4-oxadiazole
0 Intermediate 9 (lg) in l,l,l-triethoxyethane (lOml) was heated to
reflux for 18h. The mixture was then allowed to cool and the title
compound collected by filtration as a colourless powder (816mg) m.p.
135-137-C.
15 Intermediate 11
2-~3-Bromo-4-thYlphenvl)-5-methyl-1,3~4-oxadiazole
A solution of Intermediate 8 (2g) in methanol (20ml) containing
hydrazine hydrate (l.lml) was heated to reflux under nitrogen for
18h. On cooling a crystalIine solid was deposited which was
collected by filtration (1.20g). A sample of this material (lg) was
suspended in triethylorthoacetate (lOml~ and was heated to reflux
for 18h. The mixture was left to cool and the crystalline title
coound colleoted by filtration (535mg) m.p. 91-3-.
Intermediate 12
3-(4-~romo-3-methvll~henYl)-5-(methox~methYl)-1,2,4-oxadiazole
A so1ution of sodium methoxide (740mg) in methanol (lOml) was added
dropwise to a solution of hydroxylamine hydrochloride (950mg) in
mothanol (15ml). The mixture was stirred at 20 for lh and thon
filtered. 4-~romo-3-~othylbenzonitrlle (2.68g) was then addod to
30 the filtrate, and tho mixturo hoatodlto reflux for 18h. The solvent
was th-n evaporated giving a grey solid ~3.5g). A sample of this
material (lg) was dissolved in dry pyridine (5ml) and was treated
dropwise with methoxyacetyl chloride (0.8ml). The mixture was then
heated at reflux for 0.5h. The cooled mixture was poured into water
(30ml) and refrigerated for 1 week. The solid thus formed was
~7 ~
SB320/C
- 25 -
filtered and recrystallised from isopropanol (2ml) to give the title
compound as off-white microcrYstals (300mg) m.p.52-53.5.
Intermediate 13
_ _
4-Bromo-N-r4-D~ethoxY-3-(4-methYl-l-PiPeraZinvl)PhenY11-3-
methvlbenzamide
4-Bromo-3-methylbenzoic acid (4.86g) in an excess of thionyl
chloride (25ml) was heated at reflux for lh. The oxce~s thionyl
chloride wa~ then removed by distillation and evaporation. The
resultant acid chloride was added to a mixture of a solution of
Intermediate S (S.Og) in T~F (25ml) and sodium hydroxide (1.8g) in
- wat-r (30ml). After ~tirring, under nitrogen, overnight at room
temperature the solvent was removed by evaporation, water (40ml)
added and th- mixture extracted with dichloromethane (5x50ml), dried
nnd evaporated to give a browniorange sticky foam. This was
purif$ed by FCC eluting with sy~tem B ~970:20:10) to give the title
conDound (5.73g).
T.l.C System B (970:20:10) Rf=O.ll.
Intermediate 14
r4-rrr4-NethoxY-3-(4-methYl-l-piDerazinyl)phenYl1aminolcarbonvll-2
methvlDhenvllboronic acid~ ~
Inter ediate 13 (5.77g) was treated according to the method of
Inter~odiate 7 to give title co~Pound (1.87g) as a pale yèllow foam.
T.l.c Sy-tem B (890:100~10) Rf ~ 0.07
Intermediate lS
1-~2-Chloro-S-nitroDhenYl)-4-methylpiperazine
A mixture of 2-chloro-5-nitrobenzonam$no ~7.95g) and 2-chloro-N-(2-
- chloroethyl)-N-mothylothanamino hydroohloride ~8.86g) in
chlorobenzene ~40ml) undor nitrogon was hoated to reflux for 3 days
before cooling and diluting with dichloromethane ~60ml). The
reaction mixture was then extracted with water (2xSOOml), the
aqueous layers oombined and basified with 2N sodium hydroxide, then
extracted with dichloromethane (4x400ml). The combined, dried
extracts were concentrated in vacuo to give a dark brown oil ~7.829)
which was purified by FCC eluting with ether to give a dark brown
. - ` ~
-~ 2078~0~
` SB32 0 /C
-- 26 --
oil which crystallised upon standing. The material was di~solved in
ethanol (40ml) and boiled up with some charcoal (300mg). The hot
ethanolic suspension was filtered and concentrated in vacuo to give
the title compound as a yellow oil which crystallised on standing
(5.25g) m.p.63-64-C
Intermediate 16
4-Chloro-3-(4-methY}-l-DiDerazinyl)benzenamine
A solution of Intermediate 15 (5.06g) in ethanol (60ml) and water
(iOnl) was treated with Raney Nickel~(2g of a slurry in water) under
nitrogen. This mixture was cooled to 18-C and~treàted dropwise with
hydrazine hydrate (4ml) over 15 minutes. The resultant mixture was
stirred at room temperature for 2 hours before filtering. The
filtrate was concentrated in vaouo to give an oil which cry~tallised
t5 upon cooling. The pale brown crystalline solid was dried in vacuo
to give the title co~Pound as a brown~crystalline solid (4.36g) m.p
96-97-C
'
Inter~ediate 17
20 .r 4- r ~4-methYl-l -PiperaZiDVl ) DhellYl laminolcarbonvl~
DhenYllboronic acid ~ ~ ~
To a cooled (0-) stirred solution~of (4-carboxyphenyl)boroDic acid
(166mg) iD drv pyridine (Sml) was added thionyl chloride (0.08ml).
The`mixture was stirred for 30mins and then Intermediate 16 (225mg)
25 was added. Stirring was maintained at 20- for 18h. Water (40ml)
was added and the mixture was washed with ethy} acetate (2x40ml).
The precipitate which formed;in the aqueous~layer was collected and
dried to give the ~itle com~ound (196mg).
Tlc System A (10:8:1) Rf 0.1
30 Intermediate 18
5-~4-Bromo-3-methvlPhenvl)-3-methYl-1~2,4-thiadiazole
A solution of 4-bromo-3-methylbenzenecarbothioamide ~1.20g) in
dimethylacetamide dimethyl acetal (2ml) and dichloromethane ~30ml)
was stirred under nitrogen at room temperature for 7h. The solvent
was evaporated in vacuo to give a dark brown oil to which was added
hydroxylamine-o-sulphonic acid (0.88g), methanol (20ml) and pyridine
. : . .................... :.- : .
, . . . . .
` 5~320/C ~7~'3~
~0.83ml) and the mixture stirred at room temperature under nitrogen
for 16h. After evaporation, aqueous potassium carbonate was added
and the mixture was extracted with dichloromethane. The combined
extracts were dried and evaporated to give a brown residué which was
purified by column chromatography on silica eluting with hexane:
ethyl acetate (4:1) to give the title comPound as an orange solid
(0.8g)
T.l.c.hexane:ethyl acetate (4:1), Rf=0.52
10 Interl~ediate 19
5-(4-Bro~o-3-methvlDhenvl~-N~N-dimethYl-l~2~4-oxadiazol-3-amine
To a stirred solution of 4-bro -3 _ thylbenzoic acid (500mg) in dry
acetonitrile ~5~1) containing TEA (0.48ml) was added dropwi~e ethyl
chloroformate (0.33ml) under nitrogen. The mixture was stirred for
30mins and then N,N-dimethyl-N-hydroxyguanidine, hydrochloride
(486mg) was added and stirring wa~ maintained at 20- for 18h. 2N
sodium carbonate (30ml) was added, and the mixture ex~racted with
ethyl-acetate (2x30ml). The dried extracts were evaporated to give
a pale yellow solid. This material was chromatographed on ~ilica
gel eluting with System A (200:8:1) to give a colourless solid
(400~g). 200~g of this intermediate was dissolved in absolute
ethanol (5ml) and was treated with sodium methoxide (38mg). The
mixture was heated to reflux for 2h and was then filtered to remove
some inorganic solid. The solvent was then evaporatèd giving a
cream solid which was chromatographed on silica gel eluting with
hexane:dichloromethane ~1:21 to give the title compound as an off-
white solid ~62 ng).
T.l.c. System A ~100:8:1) Rf 0.58
Intormediate 20
_
30 2-Chloro-4-~5-methYl-1,3,4-oxadiazol-2-vl)phe w l
! ' A mixture of 3-ohloro-4-hydroxybenzoic acid hydrazide (6g) and
l,l,l-triethoxyethane (9Oml) was refluxed under nitrogen for 19.5h.
on cooling and stirring, the solid which crystallised out of the
reaction mixture was filtered off, washed well with ethyl acetate
and dried to give the title comPound (1.8g)
T.l.c. ethanol Rf 0.65.
:
,
- .
~07~
sB320/c
- 28 -
Intermediate 21
2-Chloro-4-(S-methvl-1,3,4-oxadiazol-2-yl)phenol
trifluoromethanesulphonate ester
Trifluoromethanesulphonie anhydride (0.9Sml) was added dropwise to a
solution of Intermediate 20 (lg) and pyridine (0.75ml) in
dichloromethane (19ml) at O-C under nitrogen. The reaction mixture
was stirred at room temperature for 2h. A further addition of
trifluoromethanesulphonic anhydride (O.lml) was made and the
reaetion stirred for a further l.Oh. The solution WaB poured into
hydrochloric acid (lN; lOOml), the mixture èxtracted with
diehloromethane (3xlOODl) and the dried extract evaporated to give
the title coopound as a pale orange solid (1.85g).
Assay Found: C,34.7; ~,1.8; N,8.2;
CloH6N2o4clF3s requires C,35.05; ~,1.8; N,8.2%
Intermediate 22
4-(4-Bro-3-methvlphenyll-1,2,3-thiadiazole
- A mixture of 1-(4-bromo 3-methylphenyl)ethanone ~SOOmg) and 4-
methylbenzenesulphonie acid hydrazide (437mg) was heated to reflux
20 in ethanol (lSml) containing a few 4A moleeular sieves for Sh. On
cooling, colourless needles were formed,~ which were colleeted by
filtration (577mgj. 300mg of this intermediate hydrazone were
dissolved in thionyl ehloride (2~1) and was stirred at 20- for Sh.
The mixture was neutrali~ed with 2N ~odium carbonate (40ml) and
- extracted with ethyl acetate (2x30Dl). The dried extracts were then evaporated to givo a yellow solid. Thi~ material was
ehromatographed on silica eluting with dichloromethane;hexane (1:1)
to give the title conDound as pale y llow ~olid (167mg~.
T.l.c. ethyl acetateshexane (1:4) Rf 0.52.
Intermediate 23
1-(2-MethYl-S-nitroPhenvl)-4-methvl-2,6-Piperazinedione
A suspension of N-methyliminodiaeetic acid (2.00g) in aeetic
anhydride (lOml) was stirred at room temperature for lOmin and then
heated to lSO-C for lh, after whieh time the solution had turned
dark brown. The solution was eoneentrated in vaeuo and lOml of
` s~320/c ~B785Q5
- 29 -
distillate was collected. The resulting brown gum was then treated
with 2-methyl-5-nitrobenzenamina (2.06g) suspended in toluene
(20ml). The resulting mixture was heated to 100~C for 60min before
allowing to cool overnight, giving a precipitate which was collected
by filtration. The solid was washed with cold toluene (3xlOml) and
then air-dried for 2min. The solid was then added to a flask
containing acetic anhydride (15ml), heated to 140'C for 20min to
effect complet- solution of the solid. The mixture was then allowed
to cool to 60-C before concentration, in vacuo. 10ml of distillate
was collected. The cry~talline solid which for _ d as the residue
cooled was filtered off, washed with ether, and then recrystallised
from methanol (20ml), to give the title comDound as a fine powdery
cry~talline brown solid (1.78g) m.p. 157-158-C.
ntermediate 24
1-(5-A _ o-2-DethvlDhenYl)-4-methyl_ L6~piDerazinedione
; a suspension of Intermediate 23 (1.70q~ in ethanol~water (5:2,50-1)
was added under vacuum to a ~uspension of 10~ palladium on charcoal
50~ paste~600mg~ in ethanol:water (5:2, 20ml). The resulting
suspension was stirred at room te~perature under an atmosphere of
hydrogen for~10 min. The suspension was filtered through hyflo,
~;~ concentrated in vacuo, and t~he residue was dissolved in
dichloromethane, dried, fiItered and concentrated in vacuo to give
the;title comPound a8 a cream-coloured foam (1.49g).
T.l.c system A (150:8:1), Rf 0.41.
:
Intermediate 25
4-Methvl-3-1__methYl-l-piPerazinyll benzenamine
A solution of intormediato 24 ~1.489) in dry THF ~60~1) wa- hoatod
to roflux undor nitrogon, and troatod dropwl~o wlth borano-TRF
- 30 complex (1 molar solutlon, 25.5ml). The resulting'mixture wa8
heated at reflux under nitrogen for 22h before cooling and treating
with 2N hydrochloric acid (lOml) very slowly. The mixture was then
heated to reflux for a further 2h before cooling to room temperature
and concentrating in vacuo to a volume of lOml. The residue was
diluted with 2N sodium carbonate (lOOml) and extracted with ethyl
acetate (3xlOOml). The co~bined, dried extracts were concentrated
. .
.
- . ':
---~ SB320/C ~ 0 7 8 ~ O ~
-- 30 --
in vacuo and purified by FCC eluting with system A ~150:8:1) to give
the title comDound as a crystalline pale yellow solid (922mg) m.p.
83-84c.
Analysi~ found: C,70.2; H,9.5; N,20.3;
S C12H19N3 re9uires c,70.2; H,9.3; N,20.5%
Intermediate 25 was also made by the alternativo two-step reaction
as follows:
(a) l-Methvl-4-(2-methv}-S-nitroDhenvl~piDerazine
A suspension of 2-methyl-5-nitrobenzenamine (5.25g) in chlorobenzeoe
(40ml) under nitrogen Wa8 treatcd with 2-chloro-N-(2-chloromethyl)-
N-methylethanamine hydrochloride (6.64g). The resulting mixture
was heated to reflux and stirred for~ 20 hours before cooling to
room temperature and diluting with dichloromethane ~40ml). The
organic layer was extracted with slightly aoidic water (2xl50ml),
the combined aqueous extracts basified with 2N sodium hydroxide and
then extracted with dichlors~ethane (3x250ml). The combined, dried
extraots were concentrated in vaouo to give a dar~ brown oil whioh
was purified by FCC eluting with system A (250:8sl) to give the
titl- comPound as a yellov cry-talline -olid /4.59g). m.p. 61-62C.
(b) -Methyl-3-(4-methvl-1-DiDerazinYl~benzena~iDe
; ~ A solution of the~produot of step (-) (4.5g) in ethanoI was added
under vacuum to a prehydrogenated suspension of palladium on
charcoal (10% Pd on C, 50~ paste with water, 1.4g) in ethano}: water
(5:2, 50ml). The w speD-ion wa- ~tirred at room temperature under
an atmosphere of hydrogen for 2 hours. The suspension wa- filtered
through a pad of hyflo, the filter pad washed well with
ethanol:water (4sl, 200ml) and tho oo~blned filtrat-~ ovaporated in
30 vacuo to give a gummy ~olid whi~sh was dis~olvod in diohloromothane,
dried and conoentrated in vaouo to give the title oomDound as a
pale green orystalline solid (4.052g) m.p. 82-83c
Analysis Found: C, 70.2; H, 9.S; N,20.4
C12HlgN3 requires: C, 70.2; H, 9.3; N, 20.5%
Intermediate 26
. ' `
SH320/C
- 31 - 2 ~ 7 ~ ~ QS
4-Bromo-N-;4-methyl-3-(4-methYl-l-piperazinyl)phenyl~ ide
A solution of 4-bromobenzoyl chloride (1.47g) in THF (5ml) wa~ added
to a stirred solution of Intermediate 25 (915mg) in THF (15ml) and
water (lOml) containing sodium hydroxide (350mg). The mixture was
stirred at room temperature under nitrogen for 2l/2h before adding
water (50ml) and extracting with dichloromethane (3x50ml). The
combined extracts were dried and concentrated in vacuo to give a
pale yellow foam. The foam was dissolved in dichloromethane ( 5ml)
to give a yellow solution which solidified. ~xcess dichloromethane
was removed in vacuo and ether was added (25ml). The soIid was
triturated and then filtered and dried in vacuo at 60C for 2h to
give the title compound a~ an off-white solid (1.464g), m.p. 208-
209-C.
Intermediate 27
e t h v 1 4 ~ - r r r 4 - m e t h o x v - 3 - ( 4 - ~ e t h Y 1 - 1 -
i~erazinYl)~henvllaminolcarbonY11-2-methvl r 1,1'-bi~henvl~-4-
carboxYIaté
A mixture of Intermediate 7 (l.lg), Intermediate 8 (0.68g), tetrakis
(triphenylphosphine)palladium (O) (50mg) and 2N oodium carbonate
(lOml) in DN~ (lOml) was treated according to the method of ~x~ple
10 to give the title comPound (1.15g) as a pale yellow foam.
T.l.c. syst _ A (100:8:1) Rf 0.36.
Intermediate 28~
4-Bromo-3-methYL-N-hvdrox~,rbenzimidamide
A ~olution of 4-bromo-3-methylbenzonitrile (20.0gj~ in methanol
(lOOd ) was treated with hydroxylamine hydrochloride (4x2.08g) and
pota~sium t-butoxide ~4x3.25g) ovor 6 hours and the resulting
mixture heated at r-flux for 18h. Aftor cooling, the reaction
30 mixture~was poured into wator ~800ml), thelsuopension stirred for
30min, and the white solid filtered off and dried in vacuo to give
the title compound (21.2g).
Analysi~ found : C,41.9; H,3.9; N,12.2
C8HgBrN20 requires: C,42.0; H,4.0; N, 12.2%
I
Inter~ediate 29
.
!
.
~ ~ SB320/C - 32 _ ~ ~ 7 ~ ~ O 5
3-(4-Bromo-3-methYlphenvl) -8-r (methanesulPhonvl)methvll-1,2,4-
oxadiazole
A solution of Intermediate 28 (2SOmg) in methanol (Sml) was heated
to reflux and was treated dropwise, simultaneously, with sodium
methoxide (30% in methanol, O.Sml) and methyl methylsulphonylacetate
(680mg), both diluted~ with 3ml methanol. Heating was continued for
3h then the mixture was allowed to cool and was poured into water
(75Dl). The flocculent yellow precipitate was filtered and dried to
giYe the title compound (274mg) as a cream-coloured solid m.p. 130-
132.
Intermediate 30
4-Bromo-3-methYlbenzoic acid 2-acetvlhYdrazide
A mixture of Intermediate 9 (lg)~in ethanol (20ml) containing acetic
anhydride (0.61ml) and TEA (0.9lml) was heated to reflux for 2h.
Tbe mixture was then allowed to cool and was poured into water
(150ml). Thi- gave a very fine precipitate which was collected and
dried~to give the titlo come~un~ (99lmg) m.p. }86-187.
Inter~ediate 31
2-(4-Bromo-3-methYl~henvl~-5 _ thvl-1,3,4-thiadiazole
A mixture of~Intermediate 30 (450mgj and 2,4-bis(2-methoxyphenyl)-
1,3,2,4-dithiaphosphetane-2,4-disulphide (Lawesson's reagent; 840mg)
was heated to reflux in toluene (lSml), under nitrogeh, for lh.
After cooling, the mixture was partitioned between 2N sodium
carbonate (60ml) and ethyl acetate (2x40ml). The dried extracts
were evaporated giving a pale yellow oil. Trituration of the oil
ether gave a ~olid which was purified by PCC eluting with othyl
acetateshexano ~1:4) to give tho title compound a~ a colourless
crystallino olid (382mg).
30 T.l.c. ethyl acetate:hexane (1:2) Rf 0.30.
!
Interm diate 32
3-~4-Bromo-3-methvl~henYl)-1,2,4-oxadiazole-5-methanol
A solution of Intermediate 28 (250mg) in methanol (5ml) was heated
to reflux and was treated dropwise, simultaneously, with sodium
methoxide (30% in methanol, 0.5ml) and methyl hydroxyacetate
; ~
~ :
'':
`--
~7~
ss320/c
- 33 -
(0.31ml), both diluted with methanol (3ml). Heating was maintained
for 18h, then the mixture was allowed to cool, and was added to
water (75ml). The cream coloured precipitate wa3 collected and
dried in vacuo to give the title compound (241~g) ~.p. lli-112.
S
Intermediate 33
3-l4-Bromo-3-me hYlDhenYl)-5-methYl-lH-l~2~4-triazole
A mixture of Intermediate 9 (742mg) and etbyl acetimidate,
hydrochloride (600mg) in ethanol (20nl) containing T~A (1.35ml) wa8
heated to reflux, under nitrogen, for 18h. The solvents were then
evaporated and the residue purifi-d by FCC eluting with system A
(300:8:1) to give the title comDound a~a colourless nolid (450mg).
.
T.l.c. syst _ A ~100:8:1) Rf 0.55.
Intermediate 34 ~ ~
3-~4-Bromo-3-methvlDhenYl~-1,5-dimethYl-1~-1,2,4-triazole
To a stirred~solution of Intermediate 33 ~300mg) in dry D~F ~3ml)
under nitrogen was added sodium hydride (60~ d$spersion in oil,
52mg). The ~ixture was stirred for 30 mins and then methyl iodide
(0.15ml) was added. The mixture was stirred at~20 for lh and then
water (20ml) was added and stirring maintained for a further~lh.
The solid which precipitated was collected and dried in vacuo to
give the title_comDoun_ (214mg).
T.l.c. System A ~200:8:1) Rf 0.41.
~ 25
- Intermediate 35
; 4-Fluoro-2 _ t}o~ _ na~mlne
A ~olution of 5-fluoro-2-nitrophenol (lO.Og) in dry acetone ~40ml)
under nitrogoo was troated with pota-~iu~ carbonate ~8.9g). The
mixture formed a deop red ooloured thick precipitate. Methyl iodide
30 ~5ml, 11.49) was added slowly and the mixture stirred overnight and
then at 60C for 3 hours. Purther methyl iodide ~3~1, 6.84g) was
added and the mixture stirred at 60~C for a further 3 hours. After
this time the deep red colour had disappeared, and the mixture ~now
orange) WaB added to water ~SOml) and sodium hydroxide ~2N, 40ml),
and extracted with dichloromethane ~3xlOOml). The coDbined, dried
extracts were concentrated in vacuo to give a yellow oil which upon
- - :
-~ SB320/C 2 0 7 8 ~ O ~
- 34 -
cooling crystallised giving a pale yellow crystalline solid (4-
fluoro-2-methoxy-1-nitrobenzene 10.88g). A solution of this solid
in ethanol:water (200ml, 6:2) was added under vacuum to a
prehydrogenated suspension of palladium (10% on carbon, 50~ paste,
5 2.59) in ethanol:water (80ml, 6:2). The suspension was stirred
under an atmosphere of hydrogen for 2 hours, the suspension was
filtered through Hyflo and the filtercake washed thoroughly with
ethanol and water. The combined filtrates were concontrated in
vacuo and tho moist residue ro-ovaporatod with othanol. Tho purplo
oily residue was dissolvod in dichloromethane (200ml), driod and
concentrated _n vacuo to give the titlo co~Pou-n-d- as a dark purple
liquid. (7.73g).
Analysis:Found: C, 59.8; H, 6.1; N, 9.8
C7H8FNO requircs: C,59.6; H, 5.7 N, 9.9%
Intermediate 36
1-(4 ~ _ lPiPerazine
A ~ixture of Intormodiate 35 ~7.70g) and 2-chloro-N-~2-chloroethyl)-
N-methylethana~ine hydrochlorido (11.7g) in chlorobenzeno (60ml) was
heated to roflux and stirrod at roflux for 5 hours before cooling to
room tomperature and stirring for 60 hours. Hoating was resumed and
tho reaction maintained at reflux for 5 hours, before cooling to
room tomporature, diluting with dichloromethane (lOOml) and
extracting with water (3xlOOml). The solution was made slightly
acidic with 2N hydrochloric acid, tho aquoous extracts were thon
made basic (pH8-9) with 2N sodium hydroxido and extracted with
dichloromethane (4x75ml). Tho combined, dried extracts were
concentrated~in vaouo to give~a dark brown oily residue. This was
purified by FCC eluting with System A (300:8:1) and driod in vacuo
to givo tho titlo comPound as a dark brown oil (1.312g).
30 T.l.c. System A (150:8sl) Rf ~ 0.37
Intormediate 37
1-(4-Pluoro-2-mothoxv-5-nitrophenvl)-4-methvlpiperazine
Intermediate 36 (1.25g) was added dropwise to conc. sulphuric acid
(4ml). The mixture was stirred until complete solution of material
was effected, and then treated portionwise with potassium nitrate
: : . ~ .: :
' ~ ' ' ' :;
` ~
SB320/C
tO.712g) using a water b~th to maintain the temperature at 25c.
The resulting mixture was stirred at room temperature for 2 hours
before pouring into ice (20g). The aqueous solution was then
neutralised with 0.88 aqueous am~onia and basified (pH8) with 2N
sodium carbonate. The basic solution containing a gummy precipitate
was extracted with dichloromethane (4xlOml) and the combined, dried
extracts concentrated in vacuo to give the title_com~ound as a dark
orange oil (1.349g), which crystallised upon standing.
n.~.r. (CDC13) ~ 2.37(3H,s), 2.61(4H,br.t), 3.09(4H,br.t),
3.97(3H,s), 6.70(1H,d), 7.62(1H,d).
Intermediate 38
2-Fluoro-4 _ thoxv-5-(4-methvl~ iDerazinvl)bensenamine
A solution of Intermediate 37 ~1.30g) in ethanol:watèr (7:2, 45ml)
was added~under vacuum to a prehydrogenated suspension of palladium
on charcoal ~10~ Pd on C, 50% paste, 480mg) in etbanol:water (7:2,
18nl). The resulting suspension was stirred under an atmosphere of
hydrogen for 3 hours. The suspeDsion was filtered througb hyflo and
the filter pad washed thoroughly with ethanol. The combined
filtrate~ were concentrated in vacuo, the residue dissolved in
20 dichloromethane, dried, filter-d and concentrated in vacuo to give
the title com~ound as a purplish/brown solid (1.065g)
~n.m.r. (CDC13) ~ 2.35 (38,~8), 2.60 (48,m), 3.01 (48,m),~3.40
(28,br.s), 3.79 (3H,s), 6.43 (18,d), 6.60 (lH,d).
Inter~ediate 39
4-Bromo-N- r 2-1uoro-4-metho~g~ 5~4-methvl-1-~ erazinyl)phenvll-3-
methvlbenzaDIide
A suspension of 4-bromo-3-methylbenzoic acid (6o6mg) in thionyl
chloride (3ml) under nitrogen, was heated to r-flux for 2 hour-.
30 Xxcoss thionyl chloride was r~moved in vacuo, and the resulting oily
residue (the acid chloride) was di~Yolved in THF (5ml) and added
slowly to a stirring solution of Intermediate 38 ~657mg) in THF
(30ml) and 2N sodium hydroxide (3ml). The mixture was stirred at
room temperature for 4 hours, before pouring into water (lOOml) and
extracting with dichloromethane (3xlOOml). The combined, dried
~ ~ ' ' ' .
2~78t~
SB320/C
- 36 -
extracts were concentrated in vacuo to give the title compound as a
browD foam (940mg).
n.m.r. (cDcl3~ ~ 2.36 (3H,s~, 2.48 (3H,s~, 2.62 (4H,m~, 3.10 (4H,m~,
3.85 (3H,s), 6.70 (lH,d~, 7.52 (lH,dd~, 7.65 (lH,dl, 7.78 (2H,m),
5 7.99 (lH,d).
Inter~ediate 40
14-(5-Methvl-1,2,4-oxadiazol-3-vl)Ph nvllboronic acid
a olution of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (l.Og) in
dry T~F (8ml) containing triisopropylborate (3.5ml, 2.82g) was
cooled to -100c under nitrogen, and treated cautiously with
tert-butyllithium (8.82~1, 1.7M olution). The temperatur was
~aintained between -90c and -105C during addition. The mixture
was stirred at -100C for 20 mins after compl t addition, and then
allowed to warm to -30c. The mixture was treated slowly with water
'5 ~S~l) and allowed to warm to room temperatur , 2N sodium hydroxide
(50~1) wa~ added and the basic aqueous layer washed with
dichloromethane ~2xSOml~. The aqu ous lay r was acidifi d with 2N
hydrochloric acid (60ml) and extracted with dichloro~ethane ~4x50-1,
containing 20~ methanol). $he corbine~d, dried extracts were
concentrated in vacuo to give th titl- co ound as a pal yellow
~olid (SOOmg). m.p. 266-268C.
.
Intermediate 41 ~ -
2 -Meth~yl-4 -(2-methvl-1,3,4,-oxadiazol-5-Yl~rl,l -biphenvll-4-
carboxvlic acid
a mixture of }nt r~ediate 10 ~610mg) and 2N sodium carbonate (3~1)
in DME (10~1) wa~ treated with tetrakis(triphenylphosphine)palladium
(O) (20mg~ under nitrogen and tirred for 10 minut-- beforo troating
with 4-(carboxyphonyl)boronic acid ~400mg). The ro~ulting mixture
was heated to reflux and stirred for 24 hours before cooling to room
! temperature and pouring into IN sodium carbonate (40ml~. The
aqueous phase was washed with dichloromethane (lOOml) and then
acidified. The acidic agueous phase was xtracted with
dichloromethane:methano~ (5:1, 2xSOml) and the combined extracts
dried and concentrated in vacuo to give the title compound as a
white powdery solid (684mg) m.p. 224-225C.
.
'
- ss320~c ~ (~ 7 8 ~ ~ ~
-- 37 --
Intermediate 42
2'-Methvl-4'-(5-methYl-1,2,4-oxadiazol-3-vl)~l,1'-biphenvll-4-
carboxvlic acid
5 A mixture of 4-(carboxyphenyl?boronic acid ~150mg), Intermediate 1
( 228mg), sodium carbonate( 412mg) and tetrakis
(triphenylphosphine)palladium (O) (2lmg) in 1:1 aqueous Dl~ (2Oml)
was heated to reflux under nitrogen for 18h. The mixture was
allowed to cool, acidified with 2N hydrochloric acid and then
0 extracted with ethyl acetate (2x40ml). The dried extracts were
evaporated to give a cream-coloured solid (285mg). This was
recrystallised from isopropaDol (5ml) giving the title compound as a
fawn solid (165mg).m.p. 229-231.
Intermediate 43
15 N-Methvl-4-(2-bromo-5-nitroD~iDorazine
A suspension of 2-bromo-5-nitrobenzenamine ~26.0g) and 2-chloro-N-
(2-chloromethyl)-N-methylethanamine hydrochloride (23.0g)~ in
chlorobenzene ~150ml) wa- treated according to the method of
Intermediate 36. Purification by FCC eluting with System A (300:8:1
20 gradient to 200:8:1) gave the title compound as a brown solid
(9.4989) m.p. 100-103C.
Intermediate 44
4-Bromo-3-~4_thvl-l-DiDerazinvllbenzenamine
A suspension of Intermediate 43 (8.68g) in ethanol (80ml) and water
(20m~), under nitrogen, was treated with Raney nickel (-3g of a
slurry with water). The uspen-ion was then cooled to 17C and
maintained at a temperaturo bolow 28C during tho slow addition of
hydrazine hydrate (6ml), over 20min. Tho cooled mixturo was then
30 8tirred under nitrogen for 2 hours and filtered through Hyflo. The
filter cake was washed thoroughly with ethanol:water (280ml,' 6:1)
and the combined filtrates were concentrated in vacuo to give a
gummy solid which was dissolved in dichloromethane, dried and
concentrated in vacuo to give a dark grey/brown solid. The solid
was triturated in hexane:ether (1:1, 50ml) overnight. The solid was
filtered and dried to give the title comPound as a solid (3.28g).
~78~0S
S~320/c
- 38 -
Further product was obtained by concentration of the filtrate in
vacuo. The resultant orange solid residue was purified by FCC
eluting with System A (300:8:1) to give the title compound as a
yellow solid (3.38g).m.p. 120 - 121.5C.
Intermediate 45
3-Chloro-4-hYdroxv-N-l4-methoxy-3-(4-methyl-l-piporazinyl)
phenvllbenzamide
A mixture of 3-chloro-4-hydroxybenzoic acid (300mg) and thionyl
chloride (2ml) was treated with DME (l drop) and refluxed for lh.
Thionyl chloride was evaporated in vacuo and the residue, suspended
in THF (2ml), was added in one portion to a mixture of Intermediate
5 (385mg) in THF (2ml) and aqueous sodium hydroxide (2N; 4ml). The
mixture was stirred for lh, diluted with vater (25ml) and washed
with dichloromethane (2x100nl). The aqueous phase was neutralised
5 with hydrochloric acid (2N) and extracted with dichloromethane
(3x75m}). The~dried extract was eYaporated and the residue was
purified by FCC eluting with System ~ (240:10:1) followed by
(190:10:1) to give the title com~ound as an orange foam (140mg).
T.l.c. System B (90:10:1) Rf 0.4.
ExamDle 1
N- r 4-Methoxv-3-~(4-methvl-1-DiDerazinYl)Dhenvll-2'-methvl-4'-~5-
methvl-1,2,4-oxadiazol-3-~l)Ll,1'-biphenY11-4-carboxAcide~
A ixture of Inter ediate 1 (200mg) and Intermediate 7 (291mg) in
1:1 aqueous DME (20ml) containing sodium carbonate (276mg) and
tetrakis(triphenylphosphine)palladium (0) (18mg) was heated to
reflux Sor 18h under nitrogen. The mixture was allowed to cool and
silica gel (5g) added. the solvents were then evaporated and the
residue chromatographed on silica gel oluting with Systom A
30 (200~8s1) to givo the title comDound as a cream-coloured foam
(224mg).
T.1.c. System A (100:8:1) Rf 0.58.
Assay Found: C,68.25; H,6,1; N,13.35;
C29H3~NsO3-058H20 reguires C,68.5~; H,6.4; N.13.75%
Water Determination 2.06~ w/w _ O.58mol~ H20
- ~
sB32o~c 2 ~ 7 8 5 0 o5
_ 39 -
Si~ilarly prepared were:-
Example 2
N-r4-Methoxy-3-(4-methyl-l-piperazinYl)phenYll-2~-methyl-4~-(3-
methYl-1,2,4-oxadiazol-5-yl)~l,l'-biPhenyll-4-carboxamide a~ a pale
yellow foam (153mg).
T.l.c. sy~tem A (150:8:1) Rf 0.26
Ass~y Found: C,68.4; H,6.05; N,13.65;
C29H31N5O3Ø45H2O reguires C,68.85; H,6.35; N,13.85%
0 Water Deter ination 1.59%w/w 0.45~ol~ H2O
Fro~ a mixture of Intermediate 2 (200~g) and Intermediate 7 (291~g)
in 1:1 aqueous DME (20ml) containing ~odiu~ carbonate (276mq) and
tetrakis(triphenylphosphine)palladium (0) (18mg).
ExamDle 3
lS N-r4-tlothoxY-3-(4-~ethyl-l-Dil~er~slnyl)Dhonyll-2~-~ethyl~ 4-~-(5-
reth~l-1,3,4-oxadiasol-2-Yl?~ -bi~henyll-4-carboxa~ide as a
colourless foa~ (136mg).
T.l.c. Systen a (100:8:1) R 0;44
n.~.r. (CDC13) ~ 2.38 ~ 2.35 (6B, 2 x s), 2.65 (7B, ~ ~ 8), 3.15
(4B,m), 3.89 (3B,s), 6.88 (lB,d), 7.25 (lB,~), 7.30 (lB,dd), 7.36
(lH,d), 7.46 (2H, 1/2 Aa~BB~)~ 7.8 (lB, br.s)~ 7.88-8.01 (4B,~).
Fro~ a mixture of Inter~ediate 10 (149~g) and Inter~ediate 7 (218mg)
in 1:1 aqueous D~E (20~l) containing sodiu~ carbonate t206~g) and
s(erlphenr1pho-phin-)palladiu~ (0) (14~g).
Exa~Dle 4
N- r 4-~ethoxy-3-l4-nothyl-l-DiDerazinyl)~honyll-2~-~othyl-5~-(s-
othYl-1,3,4-ox di~zol-2-yl)~ biDhenvll-4-carboxaoido ~- an off-
whito foa~ ~259 ~g).
30 T.1.C. Syste~ A ~100:8:1) R9 0.40
Assay Found: ! C,67.55; H,6.35; N,13.2;
C29H3lN5o3-o-3H2o-o-4c2H6oolcH2cl2 reguire8
C,67.75; B,6.5; N,13.24
Water Deternination 1.08%w/w 0.3mol H20
SB320/C 2 ~ 7 ~ ~ o 5
- 40 -
From a mixture of Intermediate 11 ~200mg) and Inter~ediate 7 (291mg)in 1:1 aqueous DME (20ml) containing sodium carbonate (276mg) and
tetraki~(triphenylpho~phine)palladium (O) (18mg).
Example S
r 4'- r 5-~ethoxvmethYl)-1,2,4-oxadiazol-3 -Yl 1 -a- r 4-methoxv-3-(4-
methv1-1-piDerazinvl)phenY11-2~-methYl r 1,1~-biDhenyl1-4-carboxamide
as a colourless foam (200mg).
T.l.c. Syste~ A (100:8:1) Rf 0.42
Assay Found: C,67.2; H,6.05; N,12.7;
C30H33N504Ø35H20 requires: C,67.5; H,6.35; N,13.1%
W~t Determination 1.16%w/w - 0.~35mol% H20
Fro~ a mixture of Intermediate 12 (200mg) and Intermediate 7 (261mg)
in 1:1 aqueous DMR (20ml) containing sodium carbonate (247mg) and
tetrakis(triphenylphosphine)palladiu~ ~0) (16mg).
x~Dle 6
N- r 4-Nethoxv-3-~4-methvl-1-PiDerazinvl)DhenY11-2-methvl-4'-(5--
methvl-1,2,4-oxadiazol-3-vllllll'-biDhenyll-4-carboxamide as a
colourless foam (lOOmg).
T.l.c. System A (100:8:1) Rf 0.40
Assay Found: C,68.75; H,6.25; N,13.3;
- C2gH31N~03Ø5H20 requires C,68.75; H,6.35; N,13.8%
Fro~ a mixture of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole
(lOOmg) and Interrediate 14 (160ng) in 1:1 agueous DM~ (20ml)
c o n t a i n i n g s o d i u m c a r b o n a t e ( 1 4 6 m g ) a n d
tetr~kis(triphenylphosphine)palladium (O) (lOmg).
,
Example 7
N-14-Chloro-3-(4-~ethvl-1-DiDe~razinylL~henvll-2'-1~ethvl-4~-~5-
30 methvl-1,2,4-oxadiazol-3-vl)rl,l'-bi~henvll-4-carbosamide as a brown
foam (122mg).
T.l.c. System A (100:8:1), Rf 0.56
Assay Found. C,64.9; H,5.65; N,12.9;
C28H28,clNso2-o-5H2o~o~4c2H6o requires C,65.3; H,6.0; N,13.2%
.
.
2~7~Q~
~` SB320/C
- 41 -
From a mixture of Intermediate 1 (131mg) and Internediate 17 (194mg)
in 1:1 aqueous DME (20ml) containing sodium carbonate (181mg) and
tetrakis(triphenylphosphine)palladium (O) (12mg).
5 ~xample 8
N-r4-MethoxY-3-(4-methYl-l-piperazinyl)phenyll-2~-methyl-4~-(3-
ethvl-1,2,4-thiadia~ol-S-Yl) r 1,1'-biPhcn 11-4-carboxamido a3 a pale
yellow foam (65mg).
T.l.c. System A (100:8:1), Rf 0.42
A8say Found: C,66.15; H,6.0; N,12.8;
C2gH31N502SØ75H2o require~ C,66.05; H,6.2; N,13.3
From a mixture of Intermediate 18 (142mg) and Intermediate 7 (300mg)
in 1:1 aqueous DME (20ml) containing sodium carbonate (18Smg) and
tetrakis(triphenylphosphine)palladium (Oj (12mg).
IS Exa~ple 9
4~-13-(DimethYlamino)-l~2~4-oxadiazol-5-yll-N-r4-methoxy-3-(4-
ethvl-l-~iDerazinYl)phenY11-2~-methYl r ~ -biPhenyll-4-carboxamide
as a oream foam (54 g).
T.l.o. System A (100:8:1) Rf 0.45
Assay Found: C, 66.6S; H, 6.S; N, 14.95;
C30H34N603 H20 require~: C, 66.15; H, 6.6S; N, lS.4S~
Fro~ a mixture of Intermediate 19 (50mg) and Inter~ediate 7 (103mg)
in 1:1 aqueous DME (10ml) containing sodium carbonate t63~g) and
tetrakis(triphonylphosphine)palladium (O) (4mg).
Exa le 10
N-l4-Met~3~thvl-l-piporazinvl~phonyll-4~-l5-m thv1-1~2,4-
oxadiazol-3-Yl)r~ -biDhenyll-4-oarboxamido
A ulxturo of Int-rm diat- 7 (0.75g), 3-(4-bromophenyl)-5-m thyl-
30 1,2,4-oxadlazole ~0.49g), tetraki-(tiph-nylpho-phin-)palladium (O)
(50mg) and 2N sodium car~onate (lOml) in DME (1OD1) was h ated und r
reflux for 3 hours. on cooling, the solution was dilut-d with 2N
sodiu~ carbonate ~20ml), extract-d with ethyl acetate (3x50ml) and
the combined extracts dried. The mixture was filter-d and the
filtrate evaporated to drynes~ in vacuo. The residu- was purified
by flash column chromatography on silica eluting with System A
- SB320/C 2 0 7 8 ~ O ~
- 42 -
(100:8:1) to yield the title compound ~0.49g) as a white solid. m.p.
135-137c.
T.l.c. system A ~100:8:1) Rf 0.52.
Example 11
2~-Chloro-N- r 4-methoxv-3-(4-m~ L:~:e e~ L11-4~-(5-
methyl-1,3,4-oxadiazol-2-vl)[lll'-biPhenyll-4-carboxa~ide
a nixture of Intermediate 7 (300mg), Inter~ediate 21 ~557mg), and
sodium carbonate (86mg) in water ~Snl) and DM~ (filtered through
alumina, 5ml), was deoxygenaeed for 5min with nitrogen.
Tetrakis~triphenylphosphine)palladium ~0) ~19mg) was then added and
the reaction heated at reflux, with stirring under nitrogen for 17h.
The reaction mixture was diluted with water ~lOml) and then
extracted with dichloromethane ~3xlSnl). The combined extracts were
dried and evaporated in vacuo to give a brown solid. ~urification by
colu n chro atography on silioa and eluting with System A ~200:8:1)
gave a pale yellow solid ~130ag). This solid was taken up in
dichloro ethane and ethanol and then filtcred, evaporated in vacuo
to give the title co~Pound as a yellow solid (9lmg), n.p. 225-229-C.
T.l.c. System A ~50:8:1), Rf=0.74
Exa~Dle 12
- N-r4-Methoxy- -(4-methvl-1-piperazinvl~Phenyll-4'-(1-methYl-lH-
1,2,3-triazol-4-vl)Ll.I'-biphenvll-4-cnrboxamide
A ixtur of Intormediate 7 ~334mg), 4-(4-bromophenyl)-1-mothyl-1~-
1,2,3-triazole (140mg), tetrakis~triphenyleho~phino)palladium (0)
~20mg), aguoous sodium carbonate (2N,~ 2ml), and DM~ (8ml) was
refluxed under nitrogen for 5h. :The mixture was treated with water
(50al) and extractod with dichloroa thano (3x50al). The dried
- extract wa- ovaporated to sivo a brown ~olid which was trituratod
30 with ethortdichloro~ethano (2sl; 30ml) and purifiod by FCC oluting
with 8ystem B (240~10:1) followed by (190:10:1) to give the title
com~ound as a pale yellow solid (95mg)
T.l.c. system B (90:10:1) Rf 0.4.
n.m.r. (D4CH3OD) ~ 2.37 (3H,s), 2.66(48,br.m), 3.12 (4H, br.m), 3.86
(3H,B), 4.18(3H,~), 6.97 (aH~d)~ 7.33-/.43 (2H,m), 7.44-7.88 (4H, 2x
- . ss32 o /C
_ 4~ _ 2~785~5
1/2AA BB ), 7.95 (2H, 1/2AA BB ), 8.03 (2H, 1/2 AA BB ), 8.34
(1~,8).
~xample 13
N- r 4-Methoxv-3-(4-methvl-1-piperazin~l)PhenYll-2'-methYl-4'-(1,2,3-
thiadiazol-4-vll r 1,1'-biphenYll-4-carboxa~ide
A mixture of Intermediate 22 (121~g), Intermediate 7 (270mg),
palladium aoetate (Smg) and tri-(orthotolyl)phosphine ~lSmg) were
di#solved in DMF (2ml) and TEA (lml) and was heated to 100C under
nitrogen for 18h. The mixture was allowed to cool, and was
partitioned between water (50ml) and ethyl acetate (2x30ml). The
dried extracts were evaporated to give a bright yellow oil. This
material wa# chromatographed on silica gel eluting with System A
(200:8:1) to give the title co~Pound as a yellow foam (86mg)
T.l.c. System A ~100:8:1) Rf 0.40
As~ay Found: C, 66.55; H, 5.95; N, 12.5;
C2gH29N502S O.SH20 requires; C, 66.1; ~, 5.95; N, 13.75%
Exa~Dle 14
2'-Nothyl-N- r 4-meth~1-3-(4-methvl-1-PiDerazinvl)PhenYll-4~-(5
methv~ 3~4-oxadiazol-2-yl) r ~ -bi~henvll=4-carboxA lde
A solution of Intermediate 26 (962mg) in dry T~F (15 ) was cooled
to -75C and treated dropwise with n-buty}lithium (5.6ml of 1.56
~olar solution in hexane) under nitroqen. The resulti~g solution
- was stirred for 1.5 hours at -75C and was then treated dropwise
with triisopropylborate (2.0ml, 1.63g). The reaction mixture wa~
then allowed to warm to room temperature before treating with water
(3ml) and evaporating in vacuo to remove excoss organic solvont.
Tho agueou~ residue, containing a croam colour-d gum wa- wa-hod
thoroughly with othyl acotato b-foro noutrali-ing with 2N
hydrochloric acid. On cratching the gum, solidification occurrod.
The suspension was left to stand for 72 hours and the solid which
separate was filtered and washed with water ~2x2ml). The solid was
dried in vacuo at 60C to give a boronic acid intermediate as a
white solid (245mg) which was used without purification.
A solution of this (240mg) in DM~ (8ml) containing a sodium
carbonate (2N, 2ml) and tetra~is(triphenylphosphine)palladium (O)
2~7~
- S~320/C
- 44 -
(20mg) under nitrogen, wa~ treated with Intermediate 10 ~150mg).
The mixture was heated at reflux for 18 hours before cooling to room
temperature, adding to water (50ml) and extracting the mixture with
dichloromethane (2x50ml), and then ethyl acetate (50ml). The
combined, dried extracts were concentrated in vacuo and the residue
purified by flash column chromatography eluting with a gradient of
System A (450:8:1 to 300:8:1) gave the title comPound as a white
foam (195mg)
AsJay Found: C,70.7; 8, 6.5; N,13.8;
C2983lH5o2-o-582o reguires: C,71.0; 8, 6.5; N,14.3%
n.m.r. (CDC13) ~ 2.28 ~38,8), 2.36 (68, 2xs), 2.60 (4H,m), 2.64
(38,8), 3.0(48,m), 7.18 (lH,d), 7.25-7.4 (3H,m), 7.46 (2H,d),
7.81(1H,s), 7.91 (lH,dd), 8.0 (lH,s).
ExamPle 15
4'-(3-Amino-1,2,4-o~adiazol-5-Yl~ r4-methox~Y-_~4-methYl-l-
piperazinYllDhenyll-2~-methyl-[l~l~-biphenyll-4-carbosaDide
Sodium (0.24g) was dissolved in absolute etha'nol (lOml) under
nitrogen and bydroxyguanidine sulphate (2:1) ~salt) ~0.95g) added.
The mixture was stirred for 40 ~inutes and Intermediate 27 ~lg)
added. The mixture was heated under reflux for 20 hours and after
cooling, the solvent was evaporated in vacuo. The residue was
purified by FCC e}uting with System A ~100:8:1) and the eluate
evaporated to dryness to give the title compound ~22mg) as a pale
yellow solid. m.p. 169 - 171.
T.l.c. System A (100:8:1) Rf 0`.26.
~: :
ExamPle 16
N- r 4-Methoxv-3-(4-methvl-1-DiPerazinYl)DhenY11-2'-mothYl-4'-~5-
(mothYl~ l'-biDhonY11-4-
30 carboxamide
A mixturo of Intermediate 29 (123mg) and Intermediate'7 (189mg) in
T~A (lml) and DMF (2ml) containing palladium acetate (5mg) and tri-
o-tolylphosphine (15mg) was treated according to the method of
Example 13, to give the title comPound as a buff powder (68mg) m.p.
146-148
T.l.c. system A (100:8:1) Rf 0.41
' - ' ~
.
~ S~320/c 207~0~
- 45 -
Example 17
N- [ 4-Methoxy-3-(4-methvl-1-piDerazinyl)phenY~LL_2'-methYl-4'-(5-
ethYl-1,3,4-thiadiazol-2-vl~ r 1,1~ b~pb~3yl1_4_carboxamide
A mixture of Intermediate 31 (150mq), Ihtermediate 7 (ca. 30% pure
754mg) and tetrakis(triphenylphosphine)palladium (O) (20mg) in 1:1
agueous DNE (20ml) was treated according to the method of Example 1
to give the title compound as a pale yellow foam (183mg).
T.l.c. System A (100:8:1) Rf 0.38
Assay Found: - C, 64.95; H, 6.15; N, 12.5;
C29H31N502SØ8C2H6o 0.75H20 reguires:- C, 65.15; H, 6.65; N, 12.4%
ExamPle 18
4'-rS-(HYdroxymethyl)-l~2~4-oxadiazol-3-yll-N-r4-methoxv-3-(4
meth~l-l-piperazinyl)phenvll-2' _ thyl r 1,1'-biphenyll-4-c-rc~xamide
A mixture of Intermediate 7 (~258mg), Intermediate 32 ~130mg) and
tetrakis(triphenylphosphine)palladium ~0) ~lOmg) in 1:1 agueou3 DHE
~20nl) was treated according to the method of Example l to give the
title compound ~205mg) as a colourless powder m.p. 175-178.
T.l.c. System A (100:8:1) Rf 0.12.
Example 19
4'-(1,5-DimethYl-lH-1,2,4-triazol-3-Yl)-N-r4-methoxv-3-(4-meth
piPeraz1nYl)Dhenvll-2~-methvl r 1,1~-biphenvll-4-oarboxamide
25 A mixture of Intermediate 34 (144mg) and Intormediate 7 (200mg) was
heated to reflux in 1:1 agueous DHE (20ml) in the presence of sodium
carbonate (189mg) and tetrakis(tripheny1phosphine)palladium (O)
(12mg) was treated according to the method of Example 1 to give the
title comPound a8 a cream-coloured foam (83mg).
T.l.c. System A (100:8:1) Rf 0.20
Assay Found: C,68.1; H,6.6; N,15.35;
C30H34N602-0-3CH2C12 requires C,67.9; H,6.5; N,15.65%
Examp~le 20
N-r4-HYdroxY-3-(4-methYl-l-piDerazinYl)phenyll-2~-methyl-4~-(5
methvl-1,2,4-oxadiazol-3- yl ) r 1,1~-biphenY11-4-carboxanide
` ~
- sB320/c - 46 - 2 ~ 7 8 ~ Q ~
A mixture of the product of Example 1 (9lmg) and pyridine
hydrochloride (2g) was heated to 180-190 for 8h. Sodium
bicarbonate (8~; 30 ml) was added and the ~ixture extracted with
dichloromethane (2x25ml). The dried extracts were evaporated to
give a dark oil. This material wa~ chromatographed on silica gel
(Merc~ 7729, lOg) eluting with System A (200:8:1) to give the title
comoound as a colourless foam (27mg).
T.l.c. system A (100:8:1) Rf 0.40.
Assay Found: C,68.15; H,6.0; N,13.8;
C2gH2gNsO3Ø5H2o requires C,68.25; H,6.15; N,14.2
Example 21
N-~4-Methoxy-3-(4-methYl-l-DiDerazinvl)DhenY11-2~-methyl-4~-(5-
ethyl-1,2,4-1H-triazol-3-vl~ r 1,1'-biphenYll-4-carboxamide
Intermediate 27 (300mg) was dissolved in methanol (lOml), heated to
reflux for 2 day- with hydrazine hydrate (0.44mlj and the ~ixture
cooled and poured into water (75ml). The solid precipitate was
collected by filtration and dried. The solid was dissolved in
etha~ol (5ml) and was heated to reflux in the presence of ethyl
acetimidate hydrochloride (156mg) and TEA (0.17ml) for 18h. The
mixture was then evaporated to dryness and the residue purified by
FCC eluting with System A l100:8:1) to give the title comDound as a
colourless foam (83mg).
T.l.o. System A (50:8:1) Rf 0.63
Assay Found C, 66.75; H, 6.7; N, 15.65;
C29H32N62- 0-4C2H60- H20 requires C, 67.15; H, 6.65; N, 15.75
.
ExamDle 22
2-Chloro-N-~4-methoxv-3-(4-me _ henY11-4'-(5-
ethYl-1,2,4 ~ iDhonvll-4-carboxamide
30 Trifluoromethanesulphonic anhydride (llOmg) was added dropwise to a
solution of Intermediate 45 (130mg) and pyridine (50mg) in
dichloromethane (2ml). The solution was stirred for lh and
evaporated. The residue was treated with Intermediate 40 (102mg),
potassium phosphate (tribasic) (212mg), dioxan (3ml) and
bis(diphenylphosphinoferrocenyl)palladium (II) chloride (5mg) and
was heated at reflux under nitrogen for 16h. The cooled mixture was
,
. .
SB320/C 2 0 7 8 5 0 5
_ 47 -
added to aqueous sodium carbonate (2N; lOml) and extracted withdichloromethane (3x20ml). The dried extract was evaporated and the
residue was purified by PCC eluting with System B (190:10:1) to give
a yellow gum. The gum was treated with ether (Sml) and evaporated
S to give the title compound as a yellow solid (35mg) m.p. 93-95
T.l.c. Sy~tem B (90:10:1) Rf 0.5.
ExamDle 23
~ N-12-Fluoro-4-methoxy-5-(4- ethYl-l-DiD razinvlLe_envll-2-methvl-4~-
(5-~ethvl-1,2,4-oxadiazol-3-Yl~ r 1/1'-biDhenvll-4-carhoY~ide ~
A mixture of Intermediate 39 (438mg) and 2M~sodium carbonate (lml)
in DME (4ml) was treated with tetrakis~triphenylphosphine)palladium
(O) (20mg). After stirring under nitrogen for 5 minutes,
Intermediate 40 ~186mg) was added. The mixture wa3 beated to reflux
~and stirred for 24 hours. Additional c~atalyst (20mg), aqueous
; ~ sodium carbonate (0.5ml) and Inter ediate 40 (45mg) was added and
the mixture heated to reflux again for 8 hours. The mixtur- was
cooled to room tèmperature and poured into lN sodium carbonate
~SOml). The aqueous layer was extracted with dichlorom-thane
~2xSO l) and the combined, dried extracts were ooncentrated in vacuo
to give a brown foam which was purified by~FCC eluting with System A
200:8:1) to give a pale pink oil which was crystallised upon
cooling. The solid was dried in vacuo at 50C for 8 hours to give
the title com~ound as a~pale pink crystalline solid (385mg). m.p.
192-193C. ~ ~
Analysis found ~ C,63.9; H,6.3; N,11.8
29H30JNso3 0-8C2H60-1-2H20 Requlres: C,64.0; H,6.5; N,12.2
:
Example 24
N- r 4-Chloro-3-~4-mothyl-1-PiPorazin~l)phenYll-2'-~ethvl-4'-~5-
30 methvl-1,2~4-oxadiazol-3-vl~rl,l~-biphenyll-4-carboxamide
~Alternative Pre~aration~
To a stirred solution of Intermediate 42 (400mg) in dry pyridine
(lOml) wa~ added dropwise thionyl chloride (O.llml). The mixture
was stirred at 20 for lh and then a solution of Intermediate 16
~307mg) in dry pyridine ~Sml) was added. Stirring was maintained
for 18h and then the mixture was partitioned between 8~ sodium
`' ` ; ~: ''':
:
. .
' "
SB320/C 2 0 7 8 ~ O ~
- 48 -
bicarbonate (50ml) and ethyl acetate (2x70ml). The dried extracts
were evaporated to give a yellow oil which was purified by FCC
eluting with System A (200:8:1~ to give the title com~ound as an
off-white foam (500mg).
T.l.c. system A (100:8:1~ Rf 0.56
Assay Found: c, 66.2; H,5.7; N, 13.55;
C28528C1Ns02. 0-25H20 reguires: c, 66.4; H, 5.65; N, 13.8%
ExamDle 25
N- r 4-chloro-3-(4-methvl-l-pi~erazinyl~phenyll-2~-methyl-4~-(5
methvl-1~3~4-oxadiazol-2-yl~ l'-biphenYIl-4-carboxamide
To a cold (0) stirred solution of Intermediate 41 (200mg) in dry
pyridine (5ml) was added thionyl chl~oride (0.06ml). The mixture was
stirred for 0.5h and then Intermediate 16 (153mg) was added. The
mixture was stirred for lh at 20 and then at 80 for 18h. The
solventa were then evaporated and the residue purified by FCC
eluting with Sy~tem A ~200:8:1) to give the title comDound as a
y llow foam (128mg).
T.l.c. System A (100:8:1) Rf 0.38
Assay Found C, 65.6; H, 5.6; N, 13.35;
C28H23ClNs2 0-5H20 requires C, 65.8; H, 5.7; N, 13.7%
- ~ Exam~le 26
N-r4-Bromo-3-(4-Dcthyl-l-pi~erazinyl)phenYll-2'methYl-4" (5-methvl-
1,2,4-oxadiazol-3-Yl~ biDhenvll-4-carboxa~ide
A su-ponsion of Intermediate 42 (300mg), in dry dichloromethane
(3ml) was cooled to 0C and treated with TEA (lml of a 1.2M ~olution
in dichloromethane). After a few minutes all material was in
solution, and this was treated slowly with ethyl chloroformate (lml
of a 1.2M olution in dichloromothane). Tho mixturo was tirrod at
room temporaturo for 1 hour beforo treating with a solution of
Intermediate 44 (280mg) in dichloromethane ~lml). After 12 hours at
room temperature the reaction was heated to 40 for 24 hours. The
mixture was then cooled to room temperature, added to water (20ml)
and extracted with dichloromethane (3x20ml). The organic extracts
were dried and concentrated in vacuo to give an orange residue
which was purified by FCC eluting with system A (200:8:1) to give a
.
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SB320/C ~ ~ 7 ~ 5 o ~
yellow solid. Thi~ was triturated in ether to give the title
compound as a yellow cry~talline solid (125g) m.p. 151-153C
analysis: Found: C, 61.8; H, 5.3; N, 12.5
c28H23BRNsO2 Requires: C, 61.5; H, 5.2; N, 12.8
S
Example 27
N- r 4-Methoxv-3-(4-methvl-1-Piperazinvl)Phenvll-2'-methvl-4'-(1,3.4-
oxadiazol-2-vl) r ~ -biPhenVl l-4-carboxamide
Intermediate 27 (300mg) was dissolved in methanol (lOml) and was
heated to reflux for 2 days with hydrazine hydrate (0.44ml). The
mixture was cooled and poured into water (7Sml). The solid
precipitate was collected by filtration (211mg) and dried. 160mg of
this material was dissolved in l,l,l-triethoxyethane (lOml) and Wd8
heated to reflux for 3h. The solvent wa~ then~evaporated giving a
brown gum. This material was purified by FCC eluting with System a
~200:8:1) to give the title compound as a pale yellow gum (43mg).
T.l.c. Syste~ A (100:8:1) Rf 0.38
assay Found: C,64.75; H,6,25; N,12.5;
C28H29Nso3-o-6c286o~l~5H2o requires: C,65.1; ~,6.65; N,13.0%
Example 28
N-[4-Methoxv-3-(4-methvl-1-Pi-eerazinvl)-2'-methvl-4'-(5-methvl-
1,2,4-oxadiazol-3-yl) r~ -biphenvll-4-carboxamide
(a) hYdrochloride
a suspension of the compound of Example 1 (4.05g) in isopropanol
(73ml) was heated, under nitrogen, at 70C to effect dissolution of
the solid. Further isopropanol (8~1) was added and heating continuod
at 76C to give a bright palo yollow solution. Concentratod
hydrochloric acid ~0.77ml) wa~ addod and the solution allowed to
30 cool, with stirring, to 40C. once crystallisation had begun, the
solution was cooled, with stirring, for a further 3 hours in an ice-
water bath. The solid was filtered, washed with isopropanol ~2xl2ml)
and dried in vacuo to give the hvdrochloride of the title compound
(4.37g) as pale cream-coloured crystals. m.p. 256C (approx).
Analysis Found: C,62.1; H,6.3; N,ll.9; Cl,S.9;
C29H31N53 HCl-l-7H2o-o.2c3H8o requires
. .
.
SB320/C 2 ~ 7 8 ~ ~ ~
- 50 -
c,62.65; H,6.5; N,12.1; Cl,6.15%.
(b) methanesul~honate
A suspension of the compound of Example 1 (3.98g) in IMS (60ml) was
5 heated, under nitrogen, to 70C to effect dissolution of the solid.
Heating was stopped and a solution of methanesulphonic acid (0.67ml)
in IMS (4~1) was added at 65C. The solution was allowed to cool,
with stirring, to 35C and was then seeded to initiate
crystallisation. ~he solution wa~ stirred for a further 1.5hours in
an ice-water bath. The solid was filtered, washed with IMS (2xl2ml)
and dried in vacuo to give the methanesulPhonate of the title
compound (4.37g~ as a white solid. m.p. 256C.
Analysis Found: C,59.4; H,6.1; N,11.4; S,5.2;
C29H31N503-cH403s.H2o reguires
C,58.9; 8,6.1; N,11.45; s,5.2%
( c ) sulDhate
A suspension of the compound of Example 1 (4.12g) in IMS (62ml) was
treated with a solution of concentrated sulphuric acid ~0.50ml) in
IMS (4ml) according to the method of Example 28~b), to give the
sul~hate of the title com~ound (4.50g) as a white solid, m.p. 207-
218C (decomp).
Analysis Found: C,58.2; N,5.7; N,11.4; S,5.1;
C29H31N503-0-9H2S04-0-1C2H604S reguires
C,58.6; H,5.6; N,11.7; S,5.4%
(d) ~hosphate
A suspension of the compound of Rxample 1 ~4.10g) in IMS ~62ml) was
treated with a solution of phosphoric acit ~0.62ml) in IMS ~4ml)
according to tho method of Example 28~b), to givo tho phos~hate of
30 the title co~pound ~4.41g) as a white solid. m.p. 206C.
Analysis Found: C,57.3; H,5.8; N,11.4; P,5.3;
C29H3lNso3-H3o4p.o.75H2o reguires
C,57.2; H,5.9; N,11.5; P,5.1%
-
SB320/C 2 ~ 7 8 3 ~ ~
- 51 -
The following examples illustrate pharmaceutical formulations
according to the invention. The term ~active ingredient~ is used
herein to represent a compound of formula (I).
PharmaceuticaI Example 1
Oral Tablet A
Active Ingredient 700mg
sodiu~ starch glycollate 10mg
Microcrystalline cellulose 50mg
Magnesium stearate 4mg ~
Sieve the active ingredient and microcrystalline cellulose
through a 40 mesh screen and blend in a appropriate blender. Sieve
the sodlum starch glycollate and maqne-ium stearate through a 60
mesh screen, add to the powder blend and blend until homogeneou~.
Compress with~appropriate punches~in an automatic tablet pre . The
tablets may be;coated with a thin polymer coat applied by the fil~
coating techniques well ~nown to those skilled in the art. Pigment~
may be incorporated in the film coat.
Pharmaceutical Example 2
Oral Tahlet
Active Ingredlent ~500mg
Lactose 100mg
Maize Starch 50mg~
Polyvinyl pyrrolidone 3mg
Sodium starch glycollate 10mg
Magnesium stearate 4mg
! 30
Tablet Weight 667mg
Sieve the active ingredient, lactose and maize starch through a
40 me~h screen and blend the powders in a suitable blender. Make an
aqueous solution of the polyvinyl pyrrolidone (5 - 10% w/v). Add
this solution to the blended powders and mix until granulated; pass
~ , :: :
-
SB320/C
- 52 -
the granulate through a 12 mesh screen and dry the granuleq in a
suitable oven or fluid bed dryer. Sieve the remaining components
through a 60 mesh screen and blend them with the dried granules.
Compreqs, using appropriate punches, on an automatic tablet press.
The tablets may be coated with a thin polymer coat applied by
film coating technigues well known to those skilled in art.
Pigment~ may be incorporated in the film coat.
Pharmaceutical Exam~le 3
10
Inhalation Cartrid~e
Active Ingredient lmg
Lactose 24mg
~ Blend active ingredient, particle size reduced to a very fine
particle size ~woight mean diameter ca. 5~m) with the lactose iD a
suitable powder blender and fill the powder blender into No. 3 hard
gelatin capsules.
The contents of the cartridges may be administered using a
powder inhaler.
Pharmaceutical ExamPle 4
Iniection Formulation
% w/v
Active ingredient 1.00
Water for injections B.P. to 100.00
Sodium chloride may be added to adjust tho tonicity of the
solution and the pH may be adju~ted to that of maximum stability
and/or to facilitate solution of tho active ingredient using dilute
30 acid or alkali,or by the addition of suitable buffer salts.
Antioxidants and metal chelating salts may also be included.
The solution is prepared, clarified and filled into appropriate
sized ampoules sealed by fusion of the glas~. The in~ection iB
sterilised by heating in an autoclave using one of the acceptable
cycles. Alternatively the solution may be sterilised by filtration
,
: ,-
" S~320/C 2 ~ 7 ~ ~ 0
- 53 -
and filled into sterile ampoules under a~eptic condition~. The
solution may be packed under an inert atmosphere of nitrogen.
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